Method of treating animals using fused imidazoheterocyclic compounds

ABSTRACT

Imidazoheterocyclic compounds having the formula: ##STR1## wherein the A ring is pyridine in any of its four positions; B is carbonyl, thioxomethyl or hydroxymethylene; Z is hydrogen, halogen, loweralkyl, hydroxy, loweralkoxy, diloweralkylamino or nitro; Ar is phenyl, pyrido, thienyl or furanyl; and W forms a wide combination of groups with B, including acids, esters, alcohols, amides and ketones. The compounds have CNS activity in a method for treating a living animal body as muscle relaxants, anticonvulsants and antianxiety agents.

This is a division, of application Ser. No. 215,170, filed July 5, 1988,which is a division of application Ser. No. 871,772 filed June 9, 1986,now U.S. Pat. No. 4,772,600 issued Sept. 20, 1988.

BACKGROUND OF THE INVENTION

1. Field of Invention.

The present invention relates to novel fused imidazoheterocyclics whichhave one substituted imidazo nitrogen and an aryl substitution on thecarbon atom between the two imidazo nitrogens, a novel process thereforand novel intermediates in the preparation thereof. Theimidazoheterocyclic compounds have CNS activity.

2. Information Disclosure Statement.

The preparation of 2-aryl-substituted imidazo [4,5-b]pyridines has beendescribed by Garmaise, D. L. and Komlossy, J. in J. ORG. CHEM. 29(1)3403-5 (1964). Unlike the present invention, the compounds have nosubstitution on the imidazo nitrogen.

Preparation of imidazopyridines having alkylaminoalkyl substitution onone imidazo nitrogen and benzyl substitution on the carbon between thetwo imidazo nitrogens (position 2) has been described in U.S. Pat. No.2,987,518. The compounds of the present invention do not havealkylaminoalkyl substitution on an imidazo nitrogen.

2-Phenyl-imidazopyridines have been disclosed in U.S. Pat. Nos.4,327,100, 4,353,909 and 3,985,891 as cardiotonics and blood pressurealtering drugs. In U.S. Pat. No. 3,985,891, one compound is substitutedin the 3-position by methyl. The compounds of the present invention aresubstituted in the 3-position by other radicals.

Benzimidazoles substituted on nitrogen by, for example,N,N-diethylacetamide, and in the two position by an ethoxybenzylradical, are disclosed in Chemical Abstracts Vol. 66, 65425g.

Benzimidazoles substituted on nitrogen by carboxylic acid ethyl esterand in the two position by a 2-pyridinyl radical are disclosed in J.Med. Chem. 1980, 23(7), 734-8 as having anti-inflammatory activity.

(2-Phenyl-1 benzimidazolyl)propionic acid having growth-stimulatingactivity in the cotton plant is disclosed in Chemical Abstracts 100,81244r (1984).

Imidazo[4,5-b]pyridines substituted in the 2-position by ##STR2## havebeen disclosed in Monatsh. Chem. (1975) 106(5), pp 1059-69 (C.A. 84,59315u) as having no significant biological activity as compared to2-(α-hydroxybenzyl)benzimidazole.

N,N-6-Trimethyl-2-(4-methylphenyl)imidazo[1,2a] pyridine-3-acetamide hasbeen disclosed in NAUNYN-SCHMIEDBERG's ARCH. PHARMACOL (1985), Vol 330,pp 248-251. In contrast to the compounds of the present invention, thecompound has a nitrogen shared by both the imidazo moiety and thepyridine moiety and the acetamide radical is on a carbon of the imidazomoiety rather than on an imidazo nitrogen.

OBJECTS AND SUMMARY OF THE INVENTION

The novel imidazoheterocyclic compounds of the present invention havethe formula: ##STR3## wherein; A represents a heterocyclic ring havingtwo of its carbon atoms held mutually with the imidazo moiety, selectedfrom the group consisting of pyridine in any of its four positionswherein nitrogen is unshared by the imidazo moiety and substituted byone or two Z radicals on a carbon not shared by the imidazo moietyselected from the group consisting of hydrogen, halogen, loweralkyl,hydroxy, loweralkoxy, diloweralkylamino or nitro;

n is 1 to 3;

R⁶ is hydrogen or loweralkyl;

Ar is selected from: ##STR4## B is selected from carbonyl, i.e. ##STR5##thioxomethyl, i.e. ##STR6## or hydroxymethylene, i.e. ##STR7## W isselected from: hydrogen, loweralkyl, (Y)₁₋₃ -phenyl, (Y)₁₋₃-phenylloweralkyl, --OR¹, --OM, --O(CH₂)_(p) --OH,

--NR² (CH₂)_(p) COOR¹, --NR² (CH₂)_(p) OR¹, --NR² (CH₂)_(P) COOM,

--NR² [(CH₂)_(p) NHC(O)R¹ ], --NR² (CH₂)_(p) Q,

--NR² (CH₂)_(p) Ar¹ wherein Ar¹ is selected from the same group as Ar,

--NR³ R⁴,

or --NR² (CH₂)_(P) NR³ R⁴, wherein R¹ and R² are selected from:Hydrogen, loweralkyl, (Y)₁₋₃ -phenyl, or (Y)₁₋₃ -phenyl-loweralkyl,

R³ and R⁴ are selected from:

hydrogen,

loweralkyl,

loweralkenyl,

cycloalkyl,

cycloalkyl-loweralkyl,

(Y)₁₋₃ -phenyl, (Y)₁₋₃ -phenyl-loweralkyl, (Y)₁₋₂ -pyridin-2, 3 or 4-yl,or

R³ and R⁴ when taken together with the adjacent nitrogen atom may form aheterocyclic amino radical selected from:

azetidin-1-yl,

piperidin-1-yl,

loweralkyl-piperidin-1-yl,

morpholin-4-yl,

4-R⁵ -piperazin-1-yl,

thiazolidin-3-yl,

with the proviso that when B is hydroxymethylene, W is always limited tohydrogen, loweralkyl, (Y)₁₋₃ -phenyl or (Y)₁₋₃ -phenyl-loweralkylwherein Y is as defined below and a further proviso that when B isthioxomethyl, W is other than (Y)₁₋₃ -phenyl, (Y)₁₋₃ -phenyl-loweralkyl,loweralkyl, --OR¹, --OM, --O(CH₂)_(p) OR¹, or hydrogen;

p is 0-3;

R⁵ is selected from loweralkyl, ##STR8## or (Y)₁₋₃ -phenyl; Q isselected from: ##STR9## wherein all of the above Y is selected fromhydrogen, halo, loweralkoxy, loweralkyl, trifluoromethyl, cyano, nitroor diloweralkylamino;

M is a pharmaceutically acceptable metal; the optical isomers, theoxides represented by>0, and the pharmaceutically acceptable acidaddition salts including hydrates and quaternary salts thereof.

The 3H-imidazo[4,5-b]pyridine derivatives encompassed by Formula I havethe formula: ##STR10##

The 1H-imidazo[4,5-b]pyridine derivatives encompassed by Formula I havethe formula: ##STR11##

The 3H-imidazo[4,5-c] pyridine derivatives encompassed by Formula I havethe formula: ##STR12##

The 1H-imidazo[4,5-c]pyridine derivatives encompassed by Formula I havethe formula: ##STR13##

In the further definitions of symbols in the formulas hereof and wherethey appear elsewhere throughout this specification and the claims, theterms have the following significance.

The term "loweralkyl" as used herein, unless otherwise specified,includes straight and branched chain radicals of up to eight carbonsinclusive and is exemplified by such groups as methyl, ethyl, propyl,isopropyl, butyl, sec. butyl, tert. butyl, amyl, isoamyl, hexyl, heptyland octyl radicals and the like. The term "loweralkoxy" has the formula-O-loweralkyl.

The term "cycloalkyl" as used herein includes primarily cyclic alkylradicals containing 3-9 carbon atoms inclusive and includes such groupsas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl,cycloheptyl and the like.

The terms "halo" or "halogen" when referred to herein include fluorine,chlorine, bromine and iodine unless otherwise stated.

"Pharmaceutically acceptable salts" include acid addition salts,hydrates, alcoholates and quaternary salts of the compounds of FormulaI, which are physiologically compatible in warm-blooded animals. Theacid addition salts may be formed by either strong or weak acids.Representative of strong acids are hydrochloric, sulfuric, andphosphoric acids. Representative of weak acids are fumaric, maleic,succinic, oxalic, citric, tartaric, hexamic and the like.

Suitable quaternary salts include the loweralkyl halides and loweralkylsulfates.

Formulas Iw, Ix, Iy, and Iz illustrate what is meant by the term, "apyridine ring in any of its four positions."

By the term "sulfurizing" is meant any agent or mixture of agents whichwill convert an amide to a thioamide such as phosphorus pentasulfide orphosphorus pentasulfide plus alkali-metal sulfide.

The compounds of Formula I are useful in the pharmaceutical method ofthis invention because of their pharmacological action on the centralnervous system. This method employs the compounds of Formula I to treata living animal body including humans for muscle tension and spasticity(i.e., to relax muscles), anxiety and convulsions. Compounds of FormulaI wherein B-W forms an acid radical, i.e., --COOH or --COOM, generallyhave weak CNS activity; however, these compounds are also chemicalintermediates in the preparation of other more active compounds.

The procedure for testing compounds for muscle relaxant activity is theMorphine-Induced-Straub-Tail-In-Mice Test. The procedure for indicatinganti-anxiety response of the compounds is the Vogel Conflict Test basedon shock-suppressed drinking behavior of rats and reaction tosubcutaneous administration of metrazole in mice. The procedure fortesting compounds for their anticonvulsant activity is based onevaluation of protective activity against seizures caused by electricalor chemical challenge. All of these evaluation techniques are describedin greater detail under Pharmacological Test Procedures hereinbelow.

It is therefore an object of the present invention to provide certainnovel imidazoheterocyclic compounds as described hereinabove and asdefined by Formula I, which have CNS activity and a process for thepreparation thereof.

Another object is to provide certain novel derivatives ofdiaminopyridines as intermediates in the preparation of theimidazoheterocyclic compounds.

Other objects are to provide methods of treatment for epilepsy, anxietyand spastic muscles.

Additional objects and advantages of the present invention will beapparent to one skilled in the art and others will become apparent fromthe following description of the best mode of carrying out the presentinvention and from the appended claims.

A schematic preparation of compounds of Formula I is given in Chart I.##STR14##

The free base of acid addition salts of Formula I compounds may beregenerated by commonly recognized procedures of partitioning betweendilute aqueous base and a suitable solvent, separating the free base inthe solvent layer, drying and evaporating the solvent.

The following process Steps 1-a, 1-b, and 2-6 each illustratepreparation of various compounds within the definition of Formula I,some of which preparations depend on the stepwise progression. Step 1-bof the process represents a novel method of obtaining a predominantisomer from a tautomeric starting material.

Step 1-a, heating a compound of the formula ##STR15## wherein x and yare alternately either carbon or nitrogen;

Ar, n, Z and R⁶ are as defined under Formula I;

B is selected from ##STR16## and when B is ##STR17## W is any radicalcapable of forming an amide with B or an --OR¹ group as defined underFormula I, except wherein R¹ is H, and when B is ##STR18## W is limitedto R¹ ; without solvent (neat) or in a suitable solvent such as ethyleneglycol to give a compound of the formula: ##STR19## wherein x, y, B, W,Ar, Z, R⁶ and n have the starting values, compounds of Formula Ia beingencompassed by Formula I;

or Step 1-b, reacting a compound of the formula ##STR20## wherein x andy are alternately either carbon or nitrogen, and Ar and Z are as definedunder Formula I in sequence with the following agents (a) and (b):

(a) base, e.g. sodium hydride or potassium carbonate in a suitablesolvent such as dimethylformamide; and

(b) a compound having the formula ##STR21## wherein B is selected from##STR22## and W, R⁶ and n are as defined under Formula I to give acompound of the formula ##STR23## wherein x and y are alternately carbonor nitrogen and W, R⁶, Z and n are as defined under Formula I, compoundsof Formula I_(c) being encompassed by Formula I;

Step 2, oxidizing a compound prepared in Steps 1-a or 1-b selected fromthose having the formula ##STR24## wherein A is a pyridine ring in anyof its 4 positions; Ar, Z, n and R⁶ are as defined above and W isloweralkyl, phenyl or phenylloweralkyl, i.e. R¹ except hydrogen, withpyridinium chlorochromate to give a compound having the formula:##STR25## wherein A, Ar, Z, R⁶, n and W have the starting values in thisstep, compounds of Formula Id being encompassed by Formula I;

Step 3, reacting a compound obtained in steps 1-a, or 1-b selected fromthose having the formula ##STR26## wherein A is a pyridine in any of its4 positions; B is ##STR27## and W forms an ester with B consistent withthe above definition of W, or a similarly prepared compound wherein W isany feasible esterifying radical;

Ar, Z, R⁶ and n are as defined above with an alkali-metal base in thepresence of water in a suitable solvent such as ethylene glycol(de-esterifying) to give a compound of the formula: ##STR28## wherein A,Ar, Z, R⁶ and n are the same as in the starting compound in this step,and M is an alkali-metal, Formula Ie being encompassed by Formula I andthereafter neutralizing the compound of Formula Ie with an acid toobtain a compound having the formula ##STR29## wherein A, Ar, Z, R⁶ andn are unchanged; Step 4, reacting and acid compound prepared in Step 3with one of the following (a), (b), or (c):

(a) 1,1'-carbonyldiimidazole,

(b) oxalyl chloride,

(c) ethyl chloroformate,

followed by reacting an amine having the formula:

    W'H

wherein W' is selected from

--NR² (CH₂)_(p) COOR¹,

--NR² (CH₂)_(p) OR¹,

--NR² (CH₂)_(p) COOM,

--NR² 8(CH₂)_(p) NHC(O)R¹ ],

--NR₂ (CH₂)_(p) Q,

--NR² (CH₂)_(p) --Ar¹,

--NR³ R⁴, or

--NR² (CH₂)_(p) NR³ R⁴, and wherein R, R², R³, R⁴, Q, Ar¹, p and M areas defined under Formula I above to give a compound having the formula:##STR30## wherein A is a pyridine ring in any of its four positions; Ar,n, Z and R⁶ are as defined above and W' has the same value as in thestarting W'H compound, compounds of Formula Ih being encompassed byFormula I;

Step 5, sulfurizing an amide prepared in Steps 1-a, I-b, or 4 wherein Bis ##STR31## and B-W forms an amide to give a thioamide of the formula:##STR32## wherein A is a pyridine in any of its four positions; Ar, Z,R⁶ and n are as defined above, and W may have any of the amine values asdefined under Formula I, compounds of Formula I_(i) being encompassed byFormula I;

Step 6, oxidizing any of the compounds prepared in Steps 1-5 withm-chloroperbenzoic acid in a anhydrous medium such as glacial aceticacid to obtain an oxide compound having the formula ##STR33## wherein A,Ar, R⁶, Z, n, B and W have the values given under Formula I above,compounds of Formula I_(j) being encompassed by Formula I.

In reference to the process steps summarized above as they apply to thepreparation of compounds of Formula I, the following description isapplicable.

In step 1-a, starting compounds of Formula II (see Chart I) wherein B is##STR34## W is OR¹ (except R¹ is never hydrogen), or W is NH₂ or anyamino radical given under the definition of Formula I and when B is##STR35## W is limited to R¹ wherein phenyl may be substituted areheated to cyclize to the imidazoheterocyclic compound. Heating (andconsequently the cyclization) may be done with or without solvent, thetemperature range encompassed thereby for all the conditions beingapproximately 100°-240° C. Water is given off during cyclization andusual methods for dehydration and collecting water may be incorporatedif desired. When the cyclization is conducted without solvent (i.e.neat) temperatures of about 180°-240° C. may be employed to bring aboutcyclization in about 5-30 minutes time. When a refluxing solvent such astoluene is used, the water is advantageously collected in a Dean-Starkapparatus and the solvent is returned to the reaction vessel. In theinstance at the boiling point of toluene of about 110° C., thecyclization is slower and may require as long as 24 hr. Strong acidcatalysts including toluene sulfonic acid are advantageously added tothe solvent to shorten the cyclization time. Ethylene glycol may also beused as solvent at higher temperatures to aid in cyclization. In thisinstance the water tends to be absorbed by the ethylene glycol and doesnot have to be driven off. If certain cyclizations, ethylene glycol maybe the preferred solvent, since the mix can be used directly in Step 3without separating the product. Thus, from the foregoing description, itmay be seen that the temperature used will depend on whether thereaction is conducted neat or with solvent and the type of solventemployed. The extent of reaction may be determined by employing TLCusing a low boiling solvent such as methylene chloride on silica baseand using Mass Spectrometer readings of the molecular weight.

In step 1-b, 2-aryl-imidazopyridine compounds in which one of theimidazo nitrogens carries a hydrogen radical is added slowly to a slurryof sodium hydride or a suitable base such as anhydrous potassiumcarbonate in a suitable carrier, preferably dimethylformamide, and themixture is heated at about 60°-90° C. for 1-2 hr. The ##STR36## compoundis added and the mixture is stirred at ambient temperature for a periodof time, usually 12-24 hr. Water is added to decompose any unreactedsodium hydride and the product is isolated by conventional crystallizingprocedures, utilizing, if necessary, evaporation of solvent, additionalsolvents and charcoal or converting to acid addition salts. The [4,5-b]and [4,5-c]-1H isomers are generally the predominant isomers formed inthis step. The isomers may be separated by crystallizing out the majorcomponent first.

In Step 2, an imidazopyridine having a secondary or tertiary alkanolside chain is oxidized by contacting it with excess pyridiniumchlorochromate in a suitable carrier such as methylene chloride at aboutroom temperature until oxidation is complete. The product is isolated bydecanting the solution, evaporation and recrystallizing from a suitablesolvent such as isopropyl alcohol.

In Step 3, imidazopyridines having a side chain terminated by an estermoiety on the imidazo nitrogen are hydrolyzed by heating with water andalkali-metal base in a suitable solvent such as ethylene glycol or analkanol such as ethanol to give a solution of alkali-metal acid salt ofthe resulting acid. The acid salt may be neutralized with any suitableacid to give the free acid which may be separated by precipitation.

In Step 4, the imidazopyridine obtained in Step 3 bearing a side chainterminated by a carboxy radical on one of the imidazo nitrogens isreacted with one of 3 reagents: 1,1'-carbonyldiimidazole, oxalylchloride, or ethyl chloroformate, followed by the desired amine. Whenthe reagent is 1,1'-carbonyldiimidazole, reaction with the acid iscarried out in a suitable carrier, preferably tetrahydrofuran, at aboutroom temperature with a stream of nitrogen gas bubbling through themixture, usually in about 2-4 hr times. The nitrogen sweeps out carbondioxide. The amine, W'H, is added and stirring is continued at roomtemperature, usually for several hours. The resulting amide is isolatedby evaporation and redissolving the residue in an appropriate solventsuch as methylene chloride followed by common crystallization methods asthe free base or an acid addition salt. When oxalyl chloride is thereagent used, it and the carboxylic acid derivative are mixed in asuitable solvent, preferably dimethylformamide, at about 5°-30° C. andthe mixture is heated at about 50°-70° C. for 3-5 hr and then added to acold solution of the W'H amine in dimethylformamide and triethylamine.The product amide is also isolated by usual techniques as the free baseor acid addition salt. When ethyl chloroformate is the reagent (seeExample 29), it and acid derivative are reacted in a suitable solvent,preferably methylene chloride usually in about 1-3 hr time at roomtemperature. The W'H amine in solvent is added slowly and the mixture isallowed to stir several hours at ambient temperature. The product amideis separated by conventional means such as evaporation, partitioningbetween dilute acid and solvent such as diethyl ether followed by columnchromatography, if necessary.

In Step 5, a compound prepared in Steps 1-a, 1-b, or 4 wherein B-W formsan amide function is optionally converted to a thioamide by sulfurizing,preferably with phosphorus pentasulfide. Acetonitrile is a suitable andpreferred carrier during sulfurization. Product thioamides are isolatedby conventional methods which may include chromatography (see Example53).

In Step 6, the imidazopyridine compounds prepared in Steps 1-5 may bereacted with m-chloroperbenzoic acid, preferably in glacial acetic acidat a temperature of about 40°-70° C. for several hours (see Examples 120and 121) to produce imidazopyrido-nitrogen oxides. The reaction mixtureis diluted with water to precipitate organic acid residue of the spentm-chloroperbenzoic acid and any peroxides are destroyed, preferably witha sulfite reagent. Product oxides are separated and purified by usualmethods.

Starting compounds of Formula II: ##STR37## wherein x and y arealternately either carbon or nitrogen, Z, Ar, R⁶ and n are as definedunder Formula I and B and W are as defined in footnote (a) of Chart Iare prepared by reactions illustrated by equations A, B and C in ChartII. ##STR38## Compounds of Formulas IIa, IIb, and IIc are encompassed byFormula II.

Procedure (B) above in Chart II represents a novel process for thepreparation of compounds of Formula IIb. Early attempts to prepare IIbcompounds stepwise by this route gave cyclized intermediates after thereduction step. The discovery that addition of ArC(O)Cl immediatelyafter reduction or cooling during the reduction and/or acylation stepsprevents the cyclization is the basis of novelty of this novel process.The method B) has application for any compound wherein R¹ is anesterifying radical of any kind, such compounds being usable to preparecompounds of Formula I as the end product independent of what theesterifying radical is.

Starting compounds of Formula III: ##STR39## wherein A, Z and Ar are asdefined under Formula I are prepared by reactions represented by theequation in Chart III. ##STR40##

The following preparations and examples serve to illustrate methods ofpreparing the compounds. The scope of the invention is not limited bythe preparations and examples; however, structures of the compounds ofthe examples are given for reference in Table 1.

PREPARATION 1 N-(3-Nitro-2-pyridinyl)glycine ethyl ester

A solution of 2-chloro-3-nitropyridine (50 g, 0.315 mole), glycine ethylester hydrochloride (220 g, 1.58 mole), and triethylamine, (155 g, 1.53mole) in 1 liter of absolute ethanol was stirred and heated to refluxovernight. The reaction mixture was evaporated to a solid mass, whichwas partitioned between water and ethyl acetate. The aqueous layer wasseparated and extracted with ethyl acetate (3×). The combined ethylacetate layer was evaporated to an oil, which was dried by azeotropicdistillation with benzene. The residue was purified by silica gelchromatography (8 cm×27 cm column) by elution with 5% methanol/95%benzene. The appropriate fractions totaled 59.2 g of the title product,m.p. 38°-9° C.

Analysis: Calculated for C₉ H₁₁ N₃ O₄ : C, 48.00; H, 4.92; N, 18.66.Found : C, 48.01; H, 4.94; N, 18.55.

PREPARATION 2 N-[3-(Benzoylamino)-2-pyridinyl]glycine ethyl ester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (1.0 g, 0.0044mole) in 140 ml of tetrahydrofuran was hydrogenated over 5% palladium oncarbon (0.2 g) at room temperature for 4 hr. The reaction mixture wasdried over magnesium sulfate and filtered through a Celite pad. To thisstirred solution was added triethylamine (0.6 g, 0.0059 mole) andbenzoyl chloride (0.62 g, 0.0044 mole). The reaction mixture was allowedto stir at room temperature overnight. The triethylamine hydrochloridewas filtered off and the filtrate was evaporated to dryness. The residuewas taken up in ether-methylene chloride solution. Sodium sulfate wasadded to adsorb an immiscible dark oil. The filtrate was evaporated todryness to give a residue which was recrystallized from ether. Theprecipitate was collected, washed with a solution of 75% hexanes/25%ether, and dried at room temperature under high vacuum to yield 1.1 g,of title compound, m.p. 115°-16° C.

Analysis: Calculated for C₁₆ H₁₇ N₃ O₃ : C, 64.20; H, 5.72; N, 14.04.Found : C, 64.05; H, 5.77; N, 14.00.

PREPARATION 3 2-[(3-Nitro-2-pyridinyl)amino]acetamide

A mixture of 2-chloro-3-nitropyridine (1.0 g, 0.0063 mole), glycinamidehydrochloride (3.11 g, 0.028 mole), triethylamine (3.1 g, 0.031 mole) in35 ml of acetonitrile was heated at reflux for 161/2 hrs. The yellowprecipitate was filtered off. The precipitate was slurried and filteredsuccessively with water, absolute alcohol and acetone. The yellow solidwas dried under high vacuum at room temperature to give 0.9 g (73.2%),of title compound, m.p. 250°-51° C. with decomposition.

Analysis: Calculated for C₉ H₈ N₄ O₃ : C, 42.86; H, 4.11; N, 28.56.Found : C, 42.84; H, 4.08; N, 28.43.

PREPARATION 4 N-[2-[[(Aminocarbonyl)methyl]amino]-3-pyridinyl]benzamide

A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (2.0 g, 0.01 mole)in 160 ml of tetrahydrofuran was hydrogenated over 5% palladium oncarbon (0.3 g) at ˜55° C. overnight. The reaction mixture was dilutedwith hot acetonitrile and dried over magnesium sulfate. The mixture wasfiltered through a Celite pad.

To the stirred filtrate under nitrogen atmosphere was addedtriethylamine (1.21 g, 0.012 mole) and benzoyl chloride (1.41 g, 0.01mole). The reaction mixture was allowed to stir at ambient temperatureovernight. The reaction mixture was evaporated to a solid residue. Thesolid was washed with methylene chloride, filtered and the filter cakewashed with methylene chloride. The solid was added to water and brokenup well with a glass rod, and the solid was again collected byfiltration. The solid was dried under high vacuum at room temperatureovernight to give 0.7 g (26%) of title compound, m.p. 194°-95° C. withdecomposition.

Analysis: Calculated for C₁₄ H₁₄ N₄ O₂ : C, 62.21; H, 5.22; N, 20.73.Found: C, 61.87; H, 5.17; N, 20.50.

PREPARATION 5 2-[(3-Amino-2-pyridinyl)amino]acetamide

A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (19.6 g, 0.1 mole)in 160 ml of ethyl acetate was hydrogenated over 5% palladium on carbon(2.0 g) at ˜55° C. overnight. The reaction mixture was warmed withacetonitrile and filtered through a Celite pad. The pad was washed withhot acetonitrile and the filtrate was evaporated to a solid. A 1.2-gsample of this solid was recrystallized from methanol-acetonitrile togive a light yellow solid, which was dried under high vacuum at roomtemperature to give 0.4 g, of title compound, m.p. 153°-55° C. withdecomposition.

Analysis: Calculated for C₇ H₁₀ N₄ O: C, 50.59; H, 6.06; N, 33.71.Found: C, 50.62; H, 6.09; N, 33.40.

PREPARATION 6 N-[3-[(2-Pyridinylcarbonyl)amino]1-2-pyridinyl]glycineethyl ester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (2.25 g, 0.01mole) was hydrogenated over 5% palladium on carbon (0.3 g) at roomtemperature for 4 hours. The reaction mixture was dried over magnesiumsulfate and the mixture was filtered through a Celite pad. The filtratewas added at room temperature over 3/4 hour to the imidazolide, whichwas prepared by adding 1,1'-carbonyldiimidazole (1.69 g, 0.01 mole) inportions to a solution of picolinic acid (1.23 g, 0.01 mole) in 100 mlof tetrahydrofuran while stirring at room temperature for 4 hours. Thereaction mixture was filtered and the filtrate was evaporated to asolid. The solid was dissolved in tetrahydrofuran and diluted withether. The supernatant liquid was decanted from the dark oil which hadformed and was evaporated. The residue was dissolved in boiling water,and the solution was filtered, and allowed to crystallize with seedingto give 0.68 g, of title compound, mp 95°-6° C.

Analysis: Calculated for C₁₅ H₁₆ N₄ O₄ : C, 59.99; H, 5.37; N, 18.66.Found: C, 59.97; H, 5.35; N, 18.58.

PREPARATION 7N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-2-pyridinecarboxamide

While bubbling nitrogen through a solution of picolinic acid (1.23 g,0.01 mole) in 100 ml of tetrahydrofuran, solid 1,1'-carbonyldiimidazole(1.62 g, 0.01 mole) was added in portions. The reaction mixture wasallowed to stir at room temperature for 5 hours. Then, a solution of2-[(3-amino-2-pyridinyl)amino]acetamide (1.66 g, 0.01 mole) inacetonitrile was added in portions to the imidazolide solution and thereaction mixture was allowed to stir at room temperature overnight. Thesolvents were evaporated. The residue completely solidified uponstanding. The solid was washed with methylene chloride and the solid wasfiltered off. The solid was recrystallized from ethyl acetate to giveseveral crops of crystals, which were combined and recrystallized fromethyl acetate to give 0.52 g of title compound, mp 188°-90° C. withdecomposition.

Analysis: Calculated for C₁₃ H₁₃ N₅ O₂ : C, 57.26; H, 4.83; N, 25.81.Found: C, 57.41; H, 4.76; N, 25.66.

PREPARATION 8 N-[3-[[(4-Chloro-2-pyridinyl)carbonyl]amino]-2-pyridinyl]glycine ethyl ester

A mixture of 4-chloro picolinic acid (7.38 g, 0.06 mole) and thionylchloride (29 ml) in 50 ml of benzene was heated at reflux for 3 to 4hrs, then evaporated to remove solvent and excess thionyl chloride. Theresidue was azeotroped with benzene (2×). The crude liquid was usedwithout purification.

Meanwhile, N-(3-nitro-2-pyridinyl)glycine ethyl ester (11.25 g, 0.05mole) dissolved in 160 ml of tetrahydrofuran was hydrogenated at roomtemperature over 5% palladium on carbon for 1 hr. The reaction mixturewas dried over sodium sulfate and filtered through a Celite pad.

The crude 4-chloro picolinoyl chloride and triethylamine (5.55 g, 0.055mole) were added dropwise simultaneously to the above stirred filtrateof N-(3-amino-2-pyridinyl)glycine ethyl ester at room temperature andallowed to stir overnight.

The reaction mixture was filtered. The tetrahydrofuran filtrate wastreated with 50 g of Florisil®, filtered, and the filtrate evaporated todryness. A 4 g sample of the dark oil was dissolved in 500 ml of hexaneand seeded to initiate crystallization. The hexane was decanted and thesolid residue was dissolved in methylene chloride and hexane, and thesolution was treated with Florisil®, and evaporated to an oil, which wascrystallized from hexane. The solid was filtered off and dried underhigh vacuum at room temperature to give 0.9 g of title compound, mp78°-80° C.

Analysis: Calculated for C₁₅ H₁₅ N₄ O₃ Cl: C, 53.82; H, 4.52; N, 16.74.Found: C, 53.81; H, 4.51; N, 16.90.

PREPARATION 9 N-[3-[(4-Methoxybenzoyl)amino]-2-pyridinyl]glycine ethylester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parrbottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hr.The reaction mixture was dried over magnesium sulfate and filteredthrough a Celite pad. A 235-ml portion of the filtrate was used in thisreaction.

Under nitrogen atmosphere, p-anisoyl chloride (9.72 g, 0.057 mole) andtriethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously tothe above-stirred filtrate at room temperature. The reaction mixture wasallowed to stir overnight. The reaction mixture was filtered and thefiltrate was treated with Florisil® (30 g), and evaporated to a solid.

The solid (˜1/2 sample) was dissolved in tetrahydrofuran and dilutedwith water. The tetrahydrofuran was boiled off and a light green solidwas collected. The solid was dissolved in tetrahydrofuran, and thesolution was decolorized with charcoal, and filtered through a Celitepad. The tetrahydrofuran solution was diluted with petroleum ether toproduce a crystalline crop. The solid was filtered off, washed withpetroleum ether, and dried under high vacuum at room temperature to give2.8 g of title compound, mp 130°-31° C.

Analysis: Calculated for C₁₇ H₁₉ N₃ O₄ : C, 62.00; H, 5.81; N, 12.76.Found: C, 62.14; H, 5.89; N, 12.61.

PREPARATION 10 N-[3-[(2-Chlorobenzoyl)amino]-2-pyridinyl]glycine ethylester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parrbottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hr.The reaction mixture was dried over magnesium sulfate and filteredthrough a Celite pad. A 235-ml portion of the filtrate was used in thisreaction.

Under nitrogen atmosphere, o-chlorobenzoyl chloride (9.97 g, 0.057 mole)and triethylamine (6.33 g, 0.063 mole) were added dropwisesimultaneously to the above-stirred filtrate at room temperature. Thereaction mixture was allowed to stir overnight, filtered, and thefiltrate was treated with Florisil® (30 g), and evaporated to a solid. A2-g portion was recrystallized from tetrahydrofuran/petroleum ether. Thesolid was collected, washed with 3:1 petroleum ether/tetrahydrofuran,and dried under high vacuum at room temperature to give 1.45 g of titlecompound, mp 111°-12° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ Cl: C, 57.58; H, 4.83; N, 12.59.Found: C, 57.62; H, 4.86; N, 12.67.

PREPARATION 11 N-[3-[(2-Methoxybenzoyl)amino]-2-pyridinyl]glycine ethylester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parrbottle over 5% palladium on carbon (6.5 g) at room temperature for 1hour. The reaction mixture was dried over magnesium sulfate and filteredthrough a Celite pad. A 235-ml portion of the filtrate was used in thisreaction. Under nitrogen atmosphere, o-anisoyl chloride (9.72 g, 0.057mole) and triethylamine (6.33 g, 0.063 mole) were added dropwisesimultaneously to the above-stirred filtrate at room temperature. Thereaction mixture was allowed to stir overnight. The reaction mixture wasfiltered, and the filtrate was treated with Florisil® (30 g), andevaporated to a solid. The solid was recrystallized from hottetrahydrofuran (minimum). The solid was filtered off, washed with coldtetrahydrofuran, and dried under high vacuum at room temperature to give5.7 g of title compound, mp 111°-12° C.

Analysis: Calculated for C₁₇ H₁₉ N₃ O₄ : C, 62.00; H, 5.81; N, 12.76.Found: C, 62.00; H, 5.81; N, 12.85.

PREPARATION 12 N-[3-[(3-Chlorobenzoyl)amino]-2-pyridinyl]glycine ethylester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parrbottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hr.The reaction mixture was dried over magnesium sulfate and filteredthrough a Celite pad. A 235-ml portion of the filtrate was used in thisreaction.

Under nitrogen atmosphere, m-chlorobenzoyl chloride (9.97 g, 0.057 mole)and triethylamine (6.33 g, 0.063 mole) were added dropwisesimultaneously to the above-stirred filtrate at room temperature. Thereaction mixture was allowed to stir overnight, filtered, and thefiltrate was treated with Florisil® (30 g), and evaporated to a solid. A2-g portion was recrystallized from tetrahydrofuran/petroleum ether. Thesolid was collected, washed with 3:1 petroleum ether/tetrahydrofuran,and dried under high vacuum at room temperature to give 1.4 g of titlecompound, mp 143°-44° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ Cl: C, 57;58; H, 4.83; N, 12.59.Found: C, 57.57; H, 4.83; N, 12.60.

PREPARATION 13 N-[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]glycine ethylester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parrbottle over 5% palladium on carbon (6.5 g) at room temperature for 1hour. The reaction mixture was dried over magnesium sulfate and filteredthrough a Celite pad. A 235-ml portion of the filtrate was used in thisreaction.

Under nitrogen atmosphere, p-chlorobenzoyl chloride (9.97 g, 0.057 mole)and triethylamine (6.33 g, 0.063 mole) were added dropwisesimultaneously to the above stirred filtrate at room temperature. Thereaction mixture was allowed to stir overnight. The reaction mixture wasfiltered, and the filtrate was treated with Florisil® (30 g), andevaporated to a solid. The solid was recrystallized fromtetrahydrofuran-water. The product was collected, washed with water, anddried under high vacuum first at 50° C. overnight, then at 65° C.overnight to give 16.5 g of title compound, mp 133°-4° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ Cl: C, 57.58; H, 4.83; N, 12.59.Found: C, 57.35; H, 4.80; N, 12.44.

PREPARATION 14N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-4-chlorobenzamide hydrate[2:1].

A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (26.0 g, 0.133mole) in 200 ml of ethyl acetate was hydrogenated over 5% palladium oncarbon (3.0 g) at 55°-60° C. for 2 hr. The reaction mixture was dilutedwith hot methanol and filtered through a Celite pad. The pad was washedseveral times with hot methanol until the filtrate was clear andcolorless. The filtrate was evaporated and dried by azeotropicevaporation of benzene (3×). The solid residue was placed under highvacuum overnight at room temperature.

To a stirred mixture of the above solid in 1 liter of acetone was addeddropwise simultaneously p-chlorobenzoyl chloride (23.28 g, 0.133 mole)and triethylamine (14.75 g, 0.146 mole). The reaction mixture wasallowed to stir overnight at room temperature. The precipitate wasfiltered off, washed with acetone, and allowed to dry under ambientconditions. The solid was dissolved in hot methanol, filtered, and thefiltrate was concentrated to produce a crystalline crop. The solid wasfiltered, washed with cold methanol and water, then dried under highvacuum at room temperature over the weekend. The sample was redriedunder high vacuum at 60° C. overnight to give 18.36 g of title compound,mp 194°-5° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₃ N₄ O₂ Cl.1/2 H₂ O: C, 53.60; H, 4.50;N, 17.86. Found: C, 53.89; H, 4.59; N, 17.75.

PREPARATION 15N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-2-chlorobenzamidehydrochloride [1:1]

A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (26.0 g, 0.133mole) in 200 ml of ethyl acetate was hydrogenated over 5% palladium oncarbon (3.0 g) at 55°-60° C. for 2 hr. The reaction mixture was dilutedwith hot methanol and filtered through a Celite pad. The pad was washedseveral times with hot methanol until the filtrate was clear andcolorless. The filtrate was evaporated and dried by azeotropicevaporation of benzene (3×). The solid residue was placed under highvacuum overnight at room temperature.

To a stirred mixture of the above solid in 1 liter of acetone was addeddropwise simultaneously o-chlorobenzoyl chloride, (23.28 g, 0.133 mole)and triethylamine (14.75 g, 0.146 mole). The reaction mixture wasallowed to stir overnight at room temperature. The reaction mixture wasfiltered and the filter cake washed with acetone and discarded. Thefiltrate and wash were evaporated to a foamy solid, which was driedunder high vacuum at room temperature. A 5-g sample was dissolved inmethanol and the solution was acidified with methanolic hydrogenchloride to slowly produce a crystalline solid. The solid was filtered,washed with cold methanol, and dried under high vacuum at roomtemperature over 3 days to give 4.33 g of title compound, mp 198°-200°C. with decomposition.

Analysis: Calculated for C₁₄ H₁₃ N₄ O₂ Cl.HCl: C, 49.28; H, 4.14; N,16.42. Found: C, 48.94; H, 4.34; N, 16.22.

PREPARATION 16 N-[3-[(3-Fluorobenzoyl)amino]-2-pyridinyl]glycine ethylester

Under a nitrogen atmosphere, 3-fluorobenzoyl chloride (12.9 g, 0.0816mole) was added dropwise to a stirred and chilled (10°-15° C.) mixtureof N-(3-amino-2-pyridinyl)glycine ethyl ester (0.0816 mole) [freshlyprepared by the hydrogenation of a solution ofN-(3-nitro-2-pyridinyl)glycine ethyl ester in tetrahydrofuran over 5%palladium on carbon at room temperature], triethylamine (8.3 g, 0.0816mole), anhydrous tetrahydrofuran (200 ml), and powdered molecularsieves. The reaction mixture was stirred at room temperature for 1 hourand was filtered. The filtrate was concentrated in vacuo and theresidual solid triturated in isopropyl ether-isopropyl alcohol, giving24.2 g (94%). Recrystallization of a 2.0-g sample gave 1.72 g of a whitepowder, mp 134°-135° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ F: C, 60.56; H, 5.08; N, 13.24.Found: C, 60.45; H, 5.07; N, 13.20.

PREPARATION 17 3-[(3-Nitro-2-pyridinyl)amino]propanoic acid ethyl esterhydrochloride [1:1]

The mixture of 2-chloro-3-nitropyridine (25.8 g, 0.16 mole), β-alanineethyl ester hydrochloride (50 g, 0.33 mole), triethylamine (49.4 g, 0.49mole), and 300 ml of absolute ethanol was warmed at 50°-55° C. for 4 hrwith mechanical stirring. The reaction mixture was evaporated and theresidue was partitioned between water and methylene chloride. The waterlayer was separated and extracted with methylene chloride (2×). Thecombined methylene chloride extracts were washed with water (2×) anddried over anhydrous sodium sulfate. The filtrate was evaporated to anorange oil (39.2 g). A 2-g sample of the oil was dissolved inacetonitrile acidified with ethereal hydrogen chloride (excess), andscratched to initiate crystallization. The yellow solid was filteredoff, washed with ether, and dried under high vacuum at room temperatureovernight to give 1.62 g of the title compound, mp 137°-40° C. (sealedtube).

Analysis: Calculated for C₁₀ H₁₃ N₃ O₄.HCl: C, 43.57; H, 5.12; N, 15.24.Found: C, 43.53; H, 5.14; N, 15.27.

PREPARATION 18 3-[(3-Nitro-2-pyridinyl)amino]propanoic acid ethyl ester

A mixture of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole), β-alanineethyl ester hydrochloride (100 g, 0.651 mole), triethylamine (103.7 g,1.03 mole) and 95% ethanol (675 ml) was refluxed for 5 hr and thenstirred at room temperature overnight. The solvent was evaporated atreduced pressure and the residue was triturated in ethyl acetate (700ml). The solid was filtered and washed with ethyl acetate. The filtratewas washed three times with water, dried over anhydrous sodium sulfate,filtered and evaporated at reduced pressure to give 113.4 g of an oil.The oil was eluted through a silica gel column (400 g) with ethylacetate. The eluent was evaporated at reduced pressure to give 106.2 gof an oil (100% yield). A small portion of the oil was crystallized frompetroleum ether to give 0.7 g of yellow solid of the title compound, mp.32.5°-33.5° C.

Analysis: Calculated for C₁₀ H₁₃ N₃ O₄ : C, 50.21; H, 5.48; N, 17.56.Found: C, 50.22; H, 5.49; N, 17.65.

PREPARATION 19 N-[3-[(4-Bromobenzoyl)amino]-2-pyridinyl]glycine ethylester

To a stirred and chilled (10°-20° C.) solution ofN-(3-amino-2-pyridinyl)glycine ethyl ester (14.7 g, 0.075 mole) [freshlyprepared by the hydrogenation of a solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester in tetrahydrofuran over 5% palladium on carbon atroom temperature], triethylamine 8.1 g, 0.080 mole), and tetrahydrofuran(150 ml) was added (rapid drop) 4-bromobenzoyl chloride (6.9 g, 0.077mole), followed by 100 ml of methylene chloride. The reaction mixturewas stirred at room temperature for 2 hr and was filtered. The filtratewas concentrated in vacuo and the residue combined with the filter cake.The combined mixture was twice suspended in water and filtered. Thefilter cake was recrystallized from ethanol, giving 22.7 g of crystals(80%). Recrystallization of a 1.6-g samples from ethanol gave 1.5 g ofwhite flocculent solid, mp 153°-154° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ Br: C, 50.81; H, 4.26; N, 11.11.Found: C, 50.47; H, 4.27; N, 11.09.

PREPARATION 203-[[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethylester

A solution of the free base of 3-[(3-nitro-2-pyridinyl)-amino]propanoicacid ethyl ester monohydrochloride, (73.2 g, 0.31 mole) in 900 ml oftetrahydrofuran was hydrogenated over 5% palladium on carbon (7.3 g) atroom temperature for 1 hr. The reaction mixture was dried over magnesiumsulfate, filtered, and the filtrate was divided into 3 equal volumes.

To this stirred filtate (1/3 volume, 0.102 mole) was addedsimultaneously triethylamine (11.33 g, 0.11 mole) and p-chlorobenzoylchloride (17.85 g, 0.102 mole). The reaction mixture was allowed to stirat room temperature overnight and filtered to remove triethylaminehydrochloride. The filtrate was treated with Florisil® (50 g), thenfiltered. The filtrate was treated with charcoal (6 g) overnight,filtered through Celite, and evaporated to a solid. A 3-g sample wasdissolved in tetrahydrofuran (minimum) and diluted with petroleum ether(bp 50°-110° C.) until crystallization was initiated. The solid wascollected and recrystallized twice from tetrahydrofuran/petroleum etherto give a light tan solid which was dried under high vacuum at 55°-60°C. to give 1.6 g of title compound, mp 124°-25° C.

Analysis: Calculated for C₁₇ H₁₈ N₃ O₃ Cl: C, 58.71; H, 5.22; N, 12.08.Found: C, 58.63; H, 5.24; N, 12.00.

PREPARATION 213-[[3-[(3-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethylester

A solution of 3-[(3-nitro-2-pyridinyl)amino]propanoic acid ethyl ester(73.2 g, 0.31 mole) in 900 ml of tetrahydrofuran was hydrogenated over5% palladium on carbon (7.3 g) at room temperature for 1 hr. Thereaction mixture was dried over magnesium sulfate, filtered, and thefiltrate was divided into 3 equal volumes.

To this stirred filtrate (1/3 volume, 0.102 mole) was addedsimultaneously triethylamine (11.33 g, 0.11 mole) and m-chlorobenzoylchloride (17.85 g, 0.102 mole). The reaction mixture was allowed to stirat room temperature overnight. The reaction mixture was filtered toremove triethylamine hydrochloride. The filtrate was treated withFlorisil® (50 g), then refiltered. The filtrate was treated withcharcoal (6 g) overnight, filtered through Celite, and evaporated todryness. A portion of the solid residue (˜3-4 g) was treated with ˜50 mlof tetrahydrofuran, filtered, and the filtrate was diluted withpetroleum ether (bp 50°-110° C.) until crystallization was inititated.The solid was collected and dried under high vacuum at 55° C. overnight.The solid was recrystallized using tetrahydrofuran-water (with methanolto eliminate phasing) with filtering to remove insoluble dark oil. Thecrystalline solid was collected, washed with water, and dried under highvacuum (50°-55° C.) overnight to give 0.55 g of title compound, mp111°-12° C.

Analysis: Calculated for C₁₇ H₁₈ N₃ O₃ Cl: C, 58.71; H, 5.22; N, 12.08.Found: C, 58.64; H, 5.26; N, 12.07.

PREPARATION 223-[[3-[(2-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethylester

A mixture of 3-[(3-nitro-2-pyridinyl)amino]propanoic acid ethyl ester(73.2 g, 0.306 mole) in 900 ml of tetrahydrofuran was hydrogenated over5% palladium on carbon (7.3 g) at room temperature for 1 hour. Thereaction mixture was dried over magnesium sulfate and filtered. Thefiltrate was divided into 3 equal parts.

To the above stirred filtrate (1/3 volume, 0.102 mole) was addeddropwise simultaneously o-chlorobenzoyl chloride (17.85 g, 0.102 mole)and triethylamine (11.33 g, 0.11 mole). The reaction mixture was allowedto stir overnight at room temperature. The reaction mixture was filteredto remove triethylamine hydrochloride. The filtrate was treated withFlorisil® (50 g), filtered, and evaporated to dryness. The dark residuewas dissolved in ethanol, diluted with water, and refrigerated overnightwith seed crystals. The dark crystalline precipitate was filtered offand dried under high vacuum at room temperature overnight. A ˜9 g samplewas heated to boiling in ˜600 ml of water and the mixture was filteredhot through a Celite pad to remove an insoluble dark oil. Thecrystalline precipitate, which formed upon cooling, was filtered off anddried under high vacuum at room temperature overnight (˜1.6 g). Thesolid was recrystallized from methanol-water. The crystallineprecipitate was filtered and dried under high vacuum at 50° C. overnightto give 0.95 g of title compound, mp 90°-92° C.

Analysis: Calculated for C₁₇ H₁₈ N₃ O₃ Cl: C, 58.71; H, 5.22; N, 12.08.Found: C, 58.80; H, 5.20; N, 12.05.

PREPARATION 23N-[2-[(2-Amino-2-oxoethyl)amino]-3-pyridinyl]-3-chlorobenzamide

A mixture of 2-[(3-nitro-2-pyridinyl)amino]acetamide (26.0 g. 0.133mole) in 200 ml of ethyl acetate was hydrogenated over 5% palladium oncarbon (3.0 g) at 55°-60° C. for 2 hours. The reaction mixture wasdiluted with hot methanol and filtered through Celite. The Celite padwas washed with hot methanol until the filtrate was colorless. Thefiltrate was evaporated to dryness and azeotropically dried withbenzene. The solid was dried under high vacuum overnight.

To a stirred mixture of the above solid in 1 liter of acetone was addeddropwise simultaneously m-chlorobenzoyl chloride (23.28 g, 0.133 mole)and triethylamine (14.75 g, 0.146 mole). The reaction mixture wasallowed to stir overnight. The precipitate was filtered off and thefilter cake was washed with acetone. The filter cake was dried underhigh vacuum overnight. The solid was dissolved in methanol (˜25 g in 1.4liter) and filtered. The clear filtrate was concentrated to ˜700 ml toproduce a crystalline precipitate; which was filtered, washed with coldmethanol and water, and dried under high vacuum at 50° C. overnight togive 11.6 g of title compound, mp 210°-11° C.

Analysis: Calculated for C₁₄ H₁₃ N₄ O₂ Cl: C, 55.18; H, 4.30; N, 18.38.Found: C, 55.15; H, 4.33; N, 18.77.

Two additional concentrations gave 18.6 g additional crystals for atotal yield of 30.2 g of product.

PREPARATION 24N-[3-[[3-(Trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester

Under a nitrogen atmosphere, 3-trifluoromethylbenzoyl chloride (15.2 g,0.073 mole) and triethylamine (7.4 g, 0.073 mole) were added dropwiseand simultaneously to a stirred and chilled (10°-15° C.) solution offreshly prepared N-[(3-amino)-2-pyridinyl]glycine ethyl ester (0.070mole), obtained by 5% palladium on carbon hydrogenation ofN-(3-nitro-2-pyridinyl)glycine ethyl ester at room temperature, in drytetrahydrofuran (200 ml). The reaction mixture was stirred overnight atroom temperature and filtered. The filtrate was concentrated in vacuoand the residue dissolved in ethyl acetate (150 ml). The ethyl acetatesolution was extracted with saturated sodium bicarbonate (3×50 ml),water (2×50 ml), dried over anhydrous sodium sulfate and concentrated togive a crude yield of 25.5 g (99%). A 3.5-g portion was recrystallizedfrom tetrahydrofuran-isopropyl ether to give 2.7 g of off-white needles,mp 129°-130° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₃ F₃ : C, 55.59; H, 4.39; N, 11.44.Found: C, 55.61; H, 4.41; N, 11.42.

PREPARATION 25 N-[3-[(3-Bromobenzoyl)amino]-2-pyridinyl]glycine

Under a nitrogen atmosphere, 3-bromobenzoyl chloride (0.10 mole)(freshly prepared) and triethylamine (10.1 g, 0.010 mole) were addeddropwise and simultaneously to a stirred and chilled (10°-15° C.)solution of freshly prepared N-[(3-amino)-2-pyridinyl]glycine ethylester (0.07 mole), obtained by 5% palladium on carbon hydrogenation ofN-(3-nitro-2-pyridinyl) glycine ethyl ester at room temperature, in drytetrahydrofuran (200 ml). The reaction mixture was stirred overnight atroom temperature and then was filtered. The filtrate was concentratedand the residue dissolved in ethyl acetate (150 ml) and washed withsaturated sodium bicarbonate (3×50 ml), water (2×50 ml), saturatedsodium chloride brine (30 ml), dried over anhydrous sodium sulfate, andconcentrated. The residue was recrystallized from isopropylalcohol-isopropyl ether giving 22 g (83%) of crystals. A 1.7-g portionwas recrystallized from isopropyl alcohol/isopropyl ether to give 1.2 gof white solid, mp 139°-140° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ Br: C, 50.81; H, 4.26; N, 11.11.Found: C, 50.76; H, 4.28; N, 11.02.

PREPARATION 26 N-[3-[(2-Pyridinylcarbonyl)amino]-2-pyridinyl]glycineethyl ester

Under a nitrogen atmosphere, triethylamine (0.30 mole) and a solution offreshly prepared acid chloride of 2-pyridine carboxylic acid (0.150mole), obtained by heating at reflux 2-pyridine carboxic acid and excessthionyl chloride in benzene and then azeotropic distillation withbenzene, in dry tetrahydrofuran (50 ml) were added simultaneously(dropwise) to a stirred and chilled (10°-20° C.) solution of freshlyprepared N-(3-amino-2-pyridinyl)glycine ethyl ester prepared by reducingN-(3-nitro-2-pyridinyl)glycine ethyl ester (0.106 mole) in 200 ml of drytetrahydrofuran. The reaction mixture was stirred overnight at roomtemperature and was filtered. The filtrate was concentrated in vacuo anddissolved in ethyl acetate (250 ml). The solution was washed withsaturated sodium bicarbonate solution (3×75 ml), water (2×75 ml), driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas crystallized from isopropyl ether-tetrahydrofuran giving 26.5 g(83%). A 3.0-g sample was twice recrystallized from isopropylether-tetrahydrofuran to give 2.4 g of a white needles, mp 98°-100° C.

Analysis: Calculated for C₁₅ H₁₆ N₄ O₃ : C, 59.99; H, 5.37; N, 18.66.Found: C, 59.86; H, 5.40; N, 18.62.

PREPARATION 27N-[3-[[4-(Trifluoromethyl)benzoyl]amino]-2-pyridinyl]glycine ethyl ester

Under a nitrogen atmosphere, triethylamine (7.4 g, 0.073 mole) and4-trifluoromethylbenzoyl chloride (15.2 g, 0.073 mole) were addedsimultaneously (dropwise) to a stirred and chilled (10°-15° C.) solutionof freshly prepared N-(3-amino-2-pyridinyl)glycine ethyl ester (0.073mole), obtained by 5% palladium on carbon hydrogenation ofN-(3-nitro-2-pyridinyl) glycine ethyl ester at room temperature, in drytetrahydrofuran (200 ml). The reaction mixture was stirred at roomtemperature for 21/2 hr and filtered. The filtrate was evaporated todryness and the residue dissolved in methylene chloride (500 ml). Thesolution was washed with saturated sodium bicarbonate solution (2×100ml), water (100 ml), dried over anhydrous sodium sulfate, andconcentrated in vacuo, giving 24.9 g (93%) of solid. A 2.0-g sample wasrecrystallized from isopropyl alcohol-isopropyl ether to give whitesolid, mp 155°-156° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₃ F₃ : C, 55.59; H, 4.39; N, 11.44.Found: C, 55.52; H, 4.40; N, 11.38.

PREPARATION 28 N-[3-[(3,4-Dichlorobenzoyl)amino]-2-pyridinyl]glycineethyl ester

A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (22.5 g, 0.1mole) in 250 ml of tetrahydrofuran was hydrogenated in a small Parrbottle over 5% palladium on carbon (2.5 g) at room temperature for 1 hr.The reaction mixture was dried over magnesium sulfate and filteredthrough a Celite pad. Under nitrogen atmosphere, 3,4-dichlorobenzoylchloride (20.95 g, 0.1 mole) and triethylamine (11.1 g, 0.11 mole) wereadded dropwise simultaneously to the above stirred filtrate at roomtemperature. After stirring overnight, the reaction mixture was filteredand the filtrate was evaporated to dryness. The residue was treated withacetone and water to obtain a crystalline solid, which was refrigeratedovernight. The solid was collected by filtration, washed with water, anddried under high vacuum at 50° C. overnight (37.1 g). A 4-g sample wasrecrystallized from acetone/water and dried under high vacuum at 50° C.for 2 days to give 2.66 g of title compound, mp 137°-38° C.

Analysis: Calculated for C₁₆ H₁₅ N₃ O₃ Cl₂ : C, 52.19; H, 4.11; N,11.41. Found: C, 52.09; H, 4.13; N, 11.44.

PREPARATION 29 N-[3-[(4-Nitrobenzoyl)amino]-2-pyridinyl]glycine ethylester

Under a nitrogen atmosphere, triethylamine (14.9 g, 0.148 mole) and4-nitrobenzoyl chloride (27.5 g, 0.148 mole) in tetrahydrofuran (25 ml)were added simultaneously (dropwise) to a stirred and chilled (5°-10°C.) solution of freshly prepared N-(3-amino-2-pyridinyl)glycine ethylester (0.14 mole), obtained by 5% palladium on carbon hydrogenation ofN-(3-nitro-2-pyridinyl) glycine ethyl ester at room temperature, in drytetrahydrofuran (140 ml). The reaction mixture was stirred at roomtemperature under nitrogen overnight and the solvent was evaporatedunder reduced pressure. The resulting solid was triturated in water (200ml) and saturated sodium bicarbonate solution (200 ml). The solid wasfiltered off, rinsed with water and dried under vacuum at 50° C. to give50.5 g (95%) of yellow solid. A 2.0-g sample was recrystallized fromisopropyl alcohol to give 1.5 g of yellow solid, mp. 151°-154° C.

Analysis: Calculated for C₁₆ H₁₆ N₄ O₅ : C, 55.81; H, 4.68; N, 16.27.Found: C, 55.81; H, 4.67; N, 16.28.

PREPARATION 30 (S)-N-(3-Nitro-2-pyridinyl)alanine hydrochloride [1:1]

A suspension of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole),(S)-alanine ethyl ester hydrochloride (100 g, 0.651 mole) andtriethylamine (103.7 g, 1.03 mole) in 95% ethanol was heated at refluxfor 4.5 hours, during which time a dark yellow solution formed. Thereaction mixture was stirred at room temperature overnight and thenrefluxed for an additional 2 hours. The solvents were evaporated underreduced pressure, and the resulting solid was triturated in ethylacetate, filtered, and rinsed with additional ethyl acetate. Thefiltrate and washings were combined and washed three times with water,dried over sodium sulfate, filtered, and evaporated to an oil weighing107 g (quantitative yield). The oil was eluted through 600 g of silicagel, using ethyl acetate as the eluent, and evaporated to an oil. A3.5-g portion of the oil was dissolved in isopropyl alcohol andacidified with ethereal hydrogen chloride. The mixture was evaporatedand redissolved in acetonitrile. Addition of isopropyl ether caused asolid to precipitate. The solid was collected by filtration and itsmother liquor was evaporated and the residue was triturated in etherealhydrogen chloride. A yellow solid formed which was collected byfiltration. Upon standing, more solid formed in the mother liquor. Thissolid was collected by filtration, rinsed with diethyl ether and driedunder high vacuum to give 0.14 g of title compound, mp >260° C. (darkens178°-185° C.).

Analysis: Calculated for C₈ H₁₀ N₃ O₄ Cl: C, 38.80; H, 4.07; N, 16.97.Found: C, 39.14; H, 4.19; N, 16.74.

PREPARATION 31 (S)-N-[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]alanineethyl ester hydrochloride[1:1]

A solution of (S)-N-(3-nitro-2-pyridinyl)alanine ethyl ester (5.0 g,0.0209 mole) in tetrahydrofuran (60 ml) was hydrogenated over 5%palladium on carbon (0.5 g) keeping the temperature of the solution atapproximately room temperature to give (S)-N-(3-amino-2-pyridinyl)alanine ethyl ester. The solution of the reduction product was cooled inan ice bath and dried over magnesium sulfate under nitrogen. Thesolution was filtered and 4-chlorobenzoyl chloride (3.84 g, 0.022 mole)and triethylamine (2.22 g, 0.022 mole) were added simultaneously,dropwise, to the cooled and stirred solution. The reaction mixture wasstirred at room temperature overnight under nitrogen and the solventswere removed under reduced pressure. The residue was partitioned betweenwater (50 ml) and ethyl acetate (50 ml). The layers were separated andthe aqueous layer was extracted again with ethyl acetate. The combinedorganic layers were washed twice with water, dried over magnesiumsulfate, treated with charcoal, filtered and evaporated to an oilweighing 6.2 g (85% yield). A 2.2-g portion of the oil was dissolved inisopropyl alcohol and the solution was acidified with ethereal hydrogenchloride. The resulting solid was filtered and dried under high vacuumto give 1.70 g of title compound, mp 172°-177° C. with decomposition.

Analysis: Calculated for C₁₇ H₁₉ N₃ O₃ Cl₂ : C, 53.14; H, 4.98; N,10.94. Found: C, 53.11; H, 5.02; N, 10.91.

PREPARATION 32 N,N,N'-Trimethyl-1,4-benzenediamine hydrochloride[1:2]

Formic acid (95-97%, 15 g, 0.326 mole) was added dropwise to aceticanhydride (27 g, 0.264 mole) at 0° C. under a nitrogen atmosphere. Theresulting solution was heated at 55° C. for 3 hours under a nitrogenatmosphere, then cooled to -20° C. and a solution ofN,N-dimethyl-1,4-phenylenediamine (13.6 g, 0.100 mole) in drytetrahydrofuran (40 ml) was added. After stirring at -20° C. for 30minutes, the solvents were removed under reduced pressure. The darkresidue was dissolved in dry tetrahydrofuran (50 ml) and the solutionwas cooled in an ice bath. Over 30 minutes, a solution of borane-methylsulfide in tetrahydrofuran (2.0M, 125 ml, 0.25 mole) was added dropwise.The ice bath was removed, and upon warming, a vigorous reactioncommenced. Upon its cessation, the solution was heated to reflux for 3hours, stirred at room temperature overnight and cooled in ice. Methanol(40 ml) was added. After the mixture was stirred at 0° C. for one hour,200 ml of methanolic hydrogen chloride solution was added to pH ≦2. Thereaction mixture was refluxed for one hour and cooled to roomtemperature. Evaporation of the solvents under reduced pressure gave adark solid residue. Water (200 ml) and sodium hydroxide pellets wereadded to pH ≧12 and the product was extracted into 3 (200-ml) portionsof diethyl ether. The combined ether layers were washed with water (200ml (3×)), dried over magnesium sulfate, charcoaled, and filtered.Evaporation of the solvents under reduced pressure gave an oily liquid(12.1 g, 80.7% yield). A 7.9-g sample of the oil was dissolved inabsolute ethanol and the solution was acidified with hydrogen chloridein methanol and hydrogen chloride in isopropyl alcohol. A solidprecipitated and was collected by filtration, rinsed with isopropylalcohol-isopropyl ether and then isopropyl ether. Drying under highvacuum gave 8.92 g of title compound, mp 207°-210° C.

Analysis: Calculated for C₉ H₁₆ N₂ Cl₂ : C, 48.44; H, 7.23; N, 12.55.Found: C, 48.44; H, 7.41; N, 12.38.

PREPARATION 33 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine

A mixture of 2,3-diaminopyridine (10.9 g, 0.1 mole), p-chlorobenzoicacid (16.0 g, 0.102 mole), and 150 g of polyphosphoric acid was heatedat 180° C. in an oil bath for 31/2 hr. The reaction mixture wasneutralized with concentrated ammonium hydroxide and bisified withsodium hydroxide. The precipitate was filtered and washed with water.The solid was treated with dilute sodium hydroxide, filtered, washedwith water, and dried under high vacuum at 60° C. overnight. A 3-gsample was dissolved in hot methanol, and the solution was treated with3 g of charcoal, and filtered through a Celite pad. The productcrystallized from the filtrate upon cooling. The precipitate wasfiltered, washed with methanol-water (2:1), and dried under high vacuumat 70° C. to give 1.0 g of the title compound, mp 305°-8° C. withsublimation.

Analysis: Calculated for C₁₂ N₈ N₃ Cl: C, 62.76; H, 3.51; N, 18.30.Found: C, 62.34; H, 3.48; N, 18.25.

PREPARATION 34 (S)-N-(3-Nitro-2-pyridinyl)alanine ethyl ester

Under a nitrogen atmosphere, triethylamine (82.1 g, 0.813 mole) wasadded to a stirred suspension of 2-chloro-3-nitropyridine (51.4 g, 0.325mole) and (S)-alanine ethyl ester hydrochloride (75 g, 0.488 mole) inabsolute ethanol (500 ml). After refluxing for 10.5 hr. and stirring atroom temperature overnight, the solvents were evaporated under reducedpressure. The residue was triturated in 500 ml of ethyl acetate,filtered, and the filter cake was rinsed with ethyl acetate. Thefiltrate was washed three times with water, dried over sodium sulfate,filtered and evaporated to an oil weighing 85.6 g. A 1.25-g sample ofthe oil was eluted through 20 g of silica gel with isopropyl ether asthe eluting solvent to give a pure fraction. The solvent was evaporatedand the residual oil was dissolved in methylene chloride, filtered, andevaporated to an oil which was dried under high vacuum at 50° C.overnight to give 0.9 g of title compound.

Analysis: Calculated for C₁₀ H₁₃ N₃ O₄ : C, 50.21; H, 5.48; N, 17.56.Found: C, 49.91; H, 5.45; N, 17.34.

PREPARATION 35 1-[(3-Nitro-2-pyridinyl)amino]-2-propanol

A mixture of 2-chloro-3-nitropyridine (10.0 g, 0.063 mole),DL-1-amino-2-propanol (7.1 g, 0.095 mole), and triethylamine (8.75 ml,0.063 mole) in absolute ethanol was heated at reflux for 11/2 hours. Thereaction mixture was evaporated to dryness and the residue waspartitioned between water and methylene chloride. The water layer wasseparated and extracted with methylene chloride (2×). The combinedmethylene chloride layers were extracted with water and dried oversodium sulfate. The filtrate was evaporated to a yellow oil. The oil waspurified on a silica gel column (200 g) eluting first with methylenechloride, followed by 5%, 10%, 25% (500 ml each), and finally 50% ethylacetate/methylene chloride. The appropriate fractions (TLC using ethylacetate) were combined and evaporated to an oil. A sample of the oil wasdried at 50°-60° C., then at 70° C. for 6 hours to give 11.9 g (96%) ofa yellow oil.

Analysis: Calculated for C₈ H₁₁ N₃ O₃ : C, 48.73; H, 5.62; N, 21.31.Found: C, 48.48; H, 5.63; N, 21.31.

PREPARATION 36 4-Chlorobenzoic acid ester with4-chloro-N-[2-[(2-hydroxypropyl) amino]3-pyridinyl]benzamide

A mixture of 1-[(3-nitro-2-pyridinyl)amino]-2-propanol (9.9 g, 0.05mole) and 5% palladium on carbon (1.0 g) in 150 ml of tetrahydrofuranwas hydrogenated in a glass Parr apparatus for 1/2 hour. The mixture wasdried over magnesium sulfate and filtered through a Celite pad to give acolorless filtrate. p-Chlorobenzoyl chloride (8.79 g, 0.05 mole) andtriethylamine (6.98 ml, 0.05 mole) were added dropwise to the stirredfiltrate at 12°-15° C. (ice bath). The reaction mixture was allowed towarm to ambient temperature overnight. The reaction mixture wasfiltered, and the filtrate was evaporated to dryness. The residue wasrecrystallized from isopropyl alcohol and water. The solid was collectedby filtration, then treated with boiling methanol. The insoluble solidwas collected by filtration, washed with methanol, and dried under highvacuum overnight to give 1.4 g of solid, mp. 186°-188° C.

Analysis: Calculated for C₂₂ H₁₉ N₃ O₃ Cl₂ : C, 59.47; H, 4.31; N, 9.46.Found: C, 59.11; H, 4.70; N, 9.36.

PREPARATION 37N-[2-[(2-Hydroxypropyl)amino]-3-pyridinyl]-4-chlorobenzamidehydrochloride[1:1]

A mixture of 1-[(3-nitro-2-pyridinyl)amino]-2-propanol (9.9 g, 0.05mole) and 5% palladium on carbon (1.0 g) in 150 ml of tetrahydrofuranwas hydrogenated in a glass Parr apparatus for 1/2 hour. The mixture wasdried over magnesium sulfate and filtered through a Celite pad to give acolorless filtrate. The p-chlorobenzoyl chloride (8.79 g, 0.05 mole) andtriethylamine (6.98 ml, 0.05 mole) were added dropwise to the stirredfiltrate at 12°-15° C. (ice bath). The reaction mixture was allowed towarm to ambient temperature overnight. The reaction mixture wasfiltered, and the filtrate was evaporated to dryness. The residue wasrecrystallized from isopropyl alcohol and water. The solid was collectedby filtration, then treated with boiling methanol. The insoluble solidwas collected by filtration, and the filtrate was evaporated to dryness,azetroped with benzene, and dried under high vacuum. The residue waspartitioned between water and methylene chloride. The methylene chloridewas extracted with 5% potassium hydroxide and water. The methylenechloride layer was dried, filtered, and evaporated to a foam. A 1.5-gsample was dissolved in ethyl acetate, acidified with ethereal andmethanolic hydrogen chloride, and seeded. The crystalline solid wascollected by filtration, washed with ethyl acetate, and dried under highvacuum to give 1.2 g of solid, mp 178°-180° C.

Analysis: Calculated for C₁₅ H₁₆ N₃ O₂ Cl.HCl: C, 52.65; H, 5.01; N,12.28. Found: C, 52.45; H, 5.24; N, 12.19.

PREPARATION 38 α-[(3-Nitro-2-pyridinylamino)methyl]benzenemethanol

A mixture of 2-chloro-3-nitropyridine (20.0 g, 0.13 mole),2-amino-1-phenylethanol (20.74 g, 0.15 mole), and triethylamine (17.5ml, 0.13 mole) in 200 ml of absolute ethanol was heated to reflux for11/2 hours. The reaction mixture was filtered and evaporated to dryness.The residue was partitioned between water and methylene chloride (2x).The methylene chloride layers were combined and extracted with water.The methylene chloride layers were dried, filtered, and evaporated to asolid (30.8 g, 94.5%). A 2.4-g sample was recrystallized from methanoland water to give a yellow solid, which was collected by filtration,washed with water, and dried under high vacuum overnight to give 1.8 gof the compound, mp 101°-103° C.

Analysis: Calculated for C₁₃ H₁₃ N₃ O₃ : C, 60.23; H, 5.05; N, 16.21.Found: C, 59.99; H, 5.26; N, 16.18.

PREPARATION 39N-[3-[(5-Bromo-2-furanylcarbonyl)amino]-2-pyridinyl]glycine ethyl esterhydrate[1:1]

Under a nitrogen atmosphere, triethylamine (32.12 g, 0.32 mole) and5-bromofuranoyl chloride (70.0 g, 0.33 mole) in tetrahydrofuran (200 ml)were added simultaneously, dropwise, to a stirred and chilled solutionof freshly prepared N-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.318mole) in dry tetrahydrofuran (˜1 liter), obtained by 5% palladium oncarbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester (71.95g, 0.318 mole) at room temperature. The reaction mixture was stirred atroom temperature under nitrogen overnight and the solvent was evaporatedunder reduced pressure. The residue was partitioned between water andethyl acetate, the layers separated and the aqueous layer was againextracted with ethyl acetate. The combined organic layers were washedwith a saturated sodium chloride solution and with water. It was driedover magnesium sulfate, charcoaled, filtered, and the solvent wasevaporated under reduced pressure to give a residue weighing 115.5 g(99%). A 5.0-g sample was recrystallized twice from isopropylalcohol/water and dried under high vacuum overnight to give 3.14 g oftitle compound, mp 78°-81° C.

Analysis: Calculated for C₁₄ H₁₆ N₃ O₅ Br: C, 43.54; H, 4.18; N, 10.88.Found: C, 43.47; H, 4.18; N, 10.62.

PREPARATION 40 (R)-N-(3-Nitro-2-pyridinyl)alanine methyl ester

A suspension of 2-chloro-3-nitropyridine (37.76 g, 0.239 mole),(R)-alanine methyl ester hydrochloride (50 g, 0.358 mole) andtriethylamine (60.3 g, 0.597 mole) in methanol (370 ml) was refluxedovernight under nitrogen. The solvents were removed under reducedpressure and the resulting solid was triturated in ethyl acetate (300ml), filtered, and rinsed with additional ethyl acetate. The filtrateand washings were combined and washed once with water. The aqueous washwas extracted with ethyl acetate and the combined organic layers werewashed several times with water, dried over sodium sulfate, filtered andevaporated under reduced pressure to given an oil weighing 45.6 g (85%).Elution of a portion of the oil with 1:6 tetrahydrofuran/hexane througha silica gel column gave 3.2 g of product after evaporation of solvent.Drying of a portion of the solid under high vacuum at room temperaturegave 0.98 g of title compound, mp 39°-40° C.

Analysis: Calculated for C₉ H₁₁ N₃ O₄ : C, 48.00; H, 4.92; N, 18.66.Found: C, 47.90; H, 4.90; N, 18.54.

PREPARATION 41 N-(3-Nitro-4-pyridinyl)glycine ethyl ester

Under a nitrogen atmosphere, a mixture of 4-chloro-3-nitropyridine (5.3g, 0.033 mole) and ethyl glycinate hydrochloride (4.67 g, 0.033 mole) in50 ml of tetrahydrofuran was treated with triethylamine (4.6 ml, 0.033mole). The reaction mixture was allowed to stir at room temperature for11/2 hours before treating with additional triethylamine (4.6 ml, 0.033mole). The tetrahydrofuran was evaporated and the residue waspartitioned between water and methylene chloride. The aqueous layer wasseparated and extracted with methylene chloride. The combined methylenechloride extracts were dried over magnesium sulfate and evaporated todryness. NMR indicated only 26% product, and the remainder startingmaterial.

The residue was dissolved in 50 ml of dioxane and treated withtriethylamine (9.2 ml, 0.066 mole) and ethyl glycinate hydrochloride(4.67 g, 0.033 mole). The reaction mixture was allowed to stir at roomtemperature overnight. The reaction mixture was partitioned betweenwater and methylene chloride. The aqueous layer was separated andextracted with methylene chloride (2×). The combined methylene chloridelayers were extracted with water, dried over magnesium sulfate, andevaporated to an oil. A portion of the oil was purified by liquidchromatography (silica gel) and elution with ethyl acetate/hexanes(1:1). The appropriate fraction by TLC (ethyl acetate) was evaporated toan oil, which crystallized. The solid was dried under high vacuum overthe weekend to give yellow solid, 1.1 g, mp 81.5°-83° C. Total yield byHPLC and silica gel filtration was 69%.

Analysis: Calculated for C₉ H₁₁ N₃ O₄ : C, 48.00; H, 4.92; N, 18.66.Found: C, 48.11; H, 4.95; N, 18.90.

PREPARATION 42N-[3-[(5-Methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester

Under a nitrogen atmosphere, triethylamine (31.41 g, 0.311 mole) and5-methyl-2-thiophenecarbonyl chloride (50 g, 0.311 mole) were addedsimultaneously, dropwise, to a stirred and chilled solution of freshlyprepared N-[[3-amino]-2-pyridinyl] glycine ethyl ester (0.296 mole) bypalladium carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethylester (66.98 g, 0.296 mole) in dry tetrahydrofuran (˜1 liter). Thereaction mixture was stirred at room temperature overnight and thesolvent was evaporated under reduced pressure. The residue waspartitioned between water and ethyl acetate, the layers separated andthe aqueous layer was again extracted with ethyl acetate. The combinedorganic layers were washed twice with a 5% potassium hydroxide solution,twice with a saturated sodium bicarbonate solution, twice with water,dried over magnesium sulfate, treated with charcoal, filtered, andevaporated under reduced pressure to give 95.3 g of a tan solid inquantitative yield. A 1.5-g portion of the solid was dissolved in hotabsolute ethanol, filtered while hot, and brought to its cloud point byaddition of water. Cooling to room temperature gave a solid which wascollected by filtration, rinsed with water, and dried under high vacuumat room temperature overnight to give 1.11 g of title compound, mp112°-115° C.

Analysis: Calculated for C₁₅ H₁₇ N₃ O₃ S: C, 56.41; H, 5.36; N, 13.16.Found: C, 56.58; H, 5.36; N, 13.02.

PREPARATION 43 N,N-Dimethyl-2-[(3-nitro-4-pyridinyl)amino]acetamide

Condensed dimethylamine (20 ml) was added in portions to a solution ofcrude N-(3-nitro-4-pyridinyl)glycine ethyl ester (4.0 g, 0.018 mole) inabsolute ethanol (10 ml). The reaction was allowed to stir at ambienttemperature over the weekend. The mixture was diluted with petroleumether and the solid was collected by filtration. The solid 3-g wasdissolved in tetrahydrofuran, filtered and diluted with isopropyl etherto produce a dark amorphous solid which was filtered off. The filtratewas further diluted with petroleum ether and placed in the freezer toproduce a dark orange crystalline solid. The solid (2.5 g) was dissolvedin methylene chloride, treated with Florisil©, and the filtrate wasevaporated to a yellow solid. which was dried under high vacuum at 70°C. to give 1.8 g (45%), mp 142°-143° C.

Analysis: Calculated for C₉ H₁₂ N₄ O₃ : C, 48.21; H, 5.39; N, 24.99.Found: C, 48.03; H, 5.36; N, 24.89.

PREPARATION 44 N-[3-[(4-Fluorobenzoyl)amino]-2-pyridinyl]glycine ethylester

Under a nitrogen atmosphere, triethylamine (31.8 g, 0.315 mole) and4-fluorobenzoyl chloride (50 g, 0.315 mole) were added simultaneously,dropwise, to a stirred and chilled solution of freshly preparedN-[[3-amino]-2-pyridinyl]glycine ethyl ester (0.33 mole) bypalladium/carbon reduction of N-[[3-nitro]-2-pyridinyl] glycine ethylester, (75.3 g, 0.33 mole) in dry tetrahydrofuran (˜800 ml). Thereaction mixture was stirred at room temperature overnight and thesolvent was evaporated under reduced pressure. The residue waspartitioned between ethyl acetate (300 ml) and water (300 ml), theinsoluble material was filtered off, the layers were separated and theaqueous layer was extracted again with ethyl acetate. The combinedorganic layer was washed three times with water, dried over magnesiumsulfate, treated with charcoal, filtered and evaporated to give 76.8 gof crude solid (77% yield). A 6.8-g portion of the solid wasrecrystallized from isopropyl alcohol and water to give 5.63 g of titlecompound, mp 127°-128.5° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ F: C, 60.56; H, 5.08; N, 13.24.Found: C, 60.19; H, 5.10; N, 13.09.

PREPARATION 45

Following the procedure of preparation 33 but substituting the followingfor 2,3-diaminopyridine:

a. 2,3-diamino-4-chloropyridine (C.A. 72, 12687d),

b. 2,3-diamino-5-chloropyridine (C.A. 72, 78970x),

c. 2,3-diamino-4,6-dichloropyridine (C.A. 72, 12687d),

d. 2,3-diamino-5-nitropyridine (C.A. 72, 3431p),

e. 2,3-diamino-6-methoxypyridine (C.A. 72, 61408x),

f. 2,3-diamino-5,6-dichloropyridine (C.A. 54, 5683d),

g. 2,3-diamino-5-bromopyridine (C.A. 61, 651a),

h. 2,3-diamino-6-chloropyridine (C.A., 61, 7763d),

i. 2,3-pyridinediamine-4-methylpyridine (U.S. Pat. No. 3,985,891),

j. 2,3-pyridinediamine-5-methylpyridine (U.S. Pat. No. 3,985,891) and

k. 2,3-pyridinediamine-6-methylpyridine (U.S. Pat. No. 3,985,891).

there are obtained:

a. 2-(4-chlorophenyl)-7-chloro-3H-imidazo[4,5-b]pyridine,

b. 2-(4-chlorophenyl)-6-chloro-3H-imidazo[4,5-b]pyridine,

c. 2-(4-chlorophenyl)-5,7-dichloro-3H-imidazo[4,5-b]pyridine,

d. 2-(4-chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine,

e. 2-(4-chlorophenyl)-5-methoxy-3H-imidazo[4,5-b]pyridine,

f. 2-(4-chlorophenyl)-5,6-dichloro-3H-imidazo[4,5-b]pyridine,

g. 2-(4-chlorophenyl)-6-bromo-3H-imidazo[4,5-b]pyridine,

h. 2-(4-chlorophenyl)-5-chloro-3H-imidazo[4,5-b]pyridine,

i. 2-(4-chlorophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine,

j. 2-(4-chlorophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine and

k. 2-(4-chlorophenyl)-5-methyl-3H-imidazo[4,5-b]pyridine.

PREPARATION 46

Following the procedure of preparation 33 but substituting the followingfor 2,3-diaminopyridine:

a. 3,4-diamino-2-methoxypyridine (C.A. 75, 62924m),

b. 3,4-diamino-5-bromo-6-chloropyridine (C.A. 58, 5676a),

c. 3,4-diaminopyridine (C.A. 66, 75975t),

d. 3,4-diamino-2-chloropyridine (C.A. 63, 5628e),

e. 3,4-diamino-2,6-dichloropyridine (C.A. 63, 5628e),

f. 3,4-diamino-5-nitropyridine (C.A. 62, 16231h),

g. 3,4-diamino-6-bromo-2-chloropyridine (C.A. 58, 5676a),

h. 3,4-diamino-5-bromopyridine (C.A. 58, 5675h) and

i. 4,5-diamino-2-chloropyridine (C.A. 63, 5628e).

there are obtained:

a. 2-(4-chlorophenyl)-4-methoxy-3H-imidazo[4,5-c]pyridine,

b. 2-4-chlorophenyl)-6-chloro-7-bromo-3H-imidazo[4,5c]pyridine,

c. 2-(4chlorophenyl)3H-imidazo[4,5-c]pyridine,

d. 2-(4-chlorophenyl)-4-chloro-3H-imidazo[4,5-c]pyridine,

e. 2-(4-chlorophenyl)-4,6-dichloro-3H-imidazo[4,5-c]pyridine,

f. 2-(4-chlorophenyl)-7-nitro-3H-imidazo[4,5-c]pyridine,

g. 2-(4-chlorophenyl)-4-chloro-6-bromo-3H-imidazo[4,5-c]pyridine,

h. 2-(4-chlorophenyl)-7-bromo-3H-imidazo[4,5-c]pyridine and

i. 2-(4-chlorophenyl)-6-chloro-1H-imidazo[4,5-c]pyridine.

PREPARATION 47

Following the procedure of preparation 1 but substituting the followingfor 2-chloro-3-nitropyridine:

a. 2-chloro-3-nitro-4-methylpyridine (C.A. 94, 15636b),

b. 2-chloro-3nitro-5-methylpyridine (C.A. 89, 6192y),

c. 2-chloro-3-nitro-6-methylpyridine (C.A. 89, 43036w),

d. 2-chloro-3-nitro-5,6-dimethylpyridine (C.A. 90, 121359r),

e. 4-chloro-6-diethylamino-2-methyl-5-nitropyridine (C.A. 88, 6799f),

f. 4-chloro-2-methyl-3-nitropyridine (C.A. 91, 20266y) and

g. 2-chloro-6-methoxy-3-nitropyridine (C.A. 77, 148422g).

there are obtained:

a. N-(4-methyl-3-nitro-2-pyridinyl)glycine ethyl ester,

b. N-(5-methyl-3-nitro-2-pyridinyl)glycine ethyl ester,

c. N-(6-methyl-3-nitro-2-pyridinyl)glycine ethyl ester,

d. N-(5,6-dimethyl-3-nitro-2-pyridinyl)glycine ethyl ester,

e. N-(6-diethylamino-2-methyl-5-nitro-4-pyridinyl)glycine ethyl ester,

f. N-(2-methyl-3-nitro-4-pyridinyl)glycine ethyl ester and

g. N-(6-methoxy-3-nitro-2-pyridinyl)glycine ethyl ester.

PREPARATION 48 a-g

Following the procedure of preparation 13 but substituting the followingfor N-(3-nitro-2-pyridinyl) glycine ethyl ester:

a. N-(4-methyl-3-nitro-2-pyridinyl)glycine ethyl ester,

b. N-(5-methyl-3-nitro-2-pyridinyl)glycine ethyl ester,

c. N-(6-methyl-3-nitro-2-pyridinyl)glycine ethyl ester,

d. N-(5,6-dimethyl-3-nitro-2-pyridinyl)glycine ethyl ester,

e. N-(6-diethylamino-2-methyl-5-nitro-4-pyridinyl)glycine ethyl ester,

f. N-(2-methyl-3-nitro-4-pyridinyl)glycine ethyl ester and

g. N-(6-methoxy3-nitro-2-pyridinyl)glycine ethyl ester.

there are obtained:

a. N-[3-(4-chlorobenzoylamino)-4-methyl-2-pyridinyl]glycine ethyl ester,

b. N-[3-(4-chlorobenzoylamino)-5-methyl-2-pyridinyl]glycine ethyl ester,

c. N-[3-(4-chlorobenzoylamino)-6-methyl-2-pyridinyl]glycine ethyl ester,

d. N-[3-(4-chlorobenzoylamino)-5,6-dimethyl-2-pyridinyl] glycine ethylester,

e.N-[5-(4-chlorobenzoylamino)-6-diethylamino-2-methyl-4-pyridinyl]glycineethyl ester,

f. N-[3-(4-chlorobenzoylamino)-2-methyl-4-pyridinyl] glycine ethyl esterand

g. N-[3-(4-chlorobenzoylamino)-6-methoxy-2-pyridinyl] glycine ethylester.

PREPARATION 49 (R)-N-[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]alaninemethyl ester

A solution of (R)-N-(3-nitro-2-pyridinyl)alanine methyl ester (21.0 g,0.0933 mole) in tetrahydrofuran (300 ml) was hydrogenated over 5%palladium on carbon (2.1 g) keeping the temperature of the solution atapproximately room temperature. The solution of the reduction productwas cooled in an ice-bath and dried over magnesium sulfate undernitrogen. The solution was filtered and 4-chlorobenzoyl chloride (17.2g, 0.0982 mole) and triethylamine (9.9 g, 0.0982 mole) were addedsimultaneously, dropwise, to the cooled and stirred solution. Afterstirring at room temperature overnight, the solvents were removed underreduced pressure and the residue was partitioned between ethyl acetate(200 ml) and water (200 ml). The layers were separated and the aqueouslayer was extracted again with ethyl acetate (100 ml). The combinedorganic layers were washed three times with water, dried over magnesiumsulfate, treated with charcoal, filtered and evaporated to give 30.9 g(99%) of product. A 3.5-g portion of the product was dissolved in hotisopropyl alcohol, treated with charcoal and filtered while hot.Petroleum ether was added to the cool solution and upon stirring, solidprecipitated, which was collected by filtration and dried under highvacuum to give 0.68 g of title compound, mp 125°-134° C.

Analysis: Calculated for C₁₆ H₁₆ N₃ O₃ Cl: C, 57.58; H, 4.83; N, 12.59.Found: C, 57.52; H, 4.85; N, 12.52.

PREPARATION 504-Chloro-N-(4-chlorobenzoyl)-N-[4-[[2-(dimethylamino)-2-oxoethyl]amino]-3-pyridinyl]benzamidehydrate [1:1]

A mixture of N,N-dimethyl-2-[(3-nitro-4-pyridinyl)amino]acetamide (11.0g, 0.05 mole) and 5% palladium on carbon catalyst (1.1 g) in 250 ml oftetrahydrofuran was hydrogenated in a small Parr apparatus while heatingat 50° C. The reaction mixture was heated with methanol and filteredthrough a Celite pad. The pad was washed with boiling methanol. Thefiltrate was evaporated to a solid. The solid was dissolved inacetonitrile (500 ml) and treated with p-chlorobenzoyl chloride (5.97ml, 0.047 mole) and triethylamine (6.52 ml, 0.047 mole). The reactionmixture was stirred at ambient temperature overnight. The reactionmixture was filtered and the filtrate was evaporated. The solid residuewas partitioned between methylene chloride and water (2×). The methylenechloride layer was dried and evaporated to dryness. The residue wasdissolved in ethyl acetate, treated with charcoal, filtered throughCelite, and concentrated. A crystalline precipitate was collected byfiltration, washed with isopropyl ether and dried at 50° C. under highvacuum to give 4.65 g of solids (40%), mp 175°-176° C.

Analysis: Calculated for C₂₃ H₂₀ N₄ O₃ Cl₂ H₂ O: C, 56.45; H, 4.53; N,11.45. Found: C, 56.03; H, 4.47; N, 11.55.

The filtrate was evaporated to dryness to give 9.24 g of crude titlecompound.

PREPARATION 514-Chloro-N-[2-[(2-hydroxy-2-phenylethyl)amino]-3-pyridinyl]benzamide

A mixture of α-[(3-nitro-2-pyridinylamino)methyl]benzene methanol (30.8g, 0.12 mole) and 5% palladium on carbon catalyst in 450 ml oftetrahydrofuran was hydrogenated in a large glass Parr bottle at roomtemperature. The reaction mixture was dried over magnesium sulfate andfiltered through a Celite pad. p-Chlorobenzoyl chloride (15.1 ml, 0.12mole) and triethylamine (16.5 ml, 0.12 mole) were added simultaneouslydropwise to the stirred filtrate at 12°-15° C. (ice-water bath) and themixture was allowed to stir at ambient temperature overnight. Thereaction mixture was filtered and the filtrate was evaporated todryness. The residue was partitioned between methylene chloride andwater. The methylene chloride layer was separated and extracted withwater (1×), 5% potassium hydroxide (2×), and water (2×). The methylenechloride layer was separated, dried, and evaporated to dryness. Theresidue was purified on a silica gel column (400 g) by eluting with 50%ethyl acetate/50% hexanes. Total recovery: 18.2 g (41.6% yield). A 5-gsample was recrystallized from ethyl acetate/hexanes to give 2.71 g ofsolid, mp. 157°-159° C.

Analysis: Calculated for C₂₀ H₁₈ N₃ O₂ Cl: C, 65.31; H, 4.93; N, 11.42.Found: C, 65.19; H, 4.95; N, 11.41.

PREPARATION 52 N-(6-Chloro-3-nitro-2-pyridinyl)glycine ethyl ester

To suspenson of 2,6-dichloro-3-nitropyridine (1.0 g, 0.00518 mole) andglycine ethyl ester hydrochloride (0.725 g, 0.00518 mole) in absoluteethanol (10 ml) was added triethylamine (1.05 g, 0.0104 mole). Theresulting solution was stirred overnight at room temperature undernitrogen. An additional portion of absolute ethanol (10 ml) was addedand the suspension was filtered and the solid was washed with 3°-10 mlportions of absolute ethanol. The combined filtrate and washings wereevaporated under reduced pressure at room temperature to give a yellowsolid which was triturated in water (30 ml) collected by filtration, andrinsed with additional water. The solid was recrystallized fromisopropyl ether/light petroleum ether, and the resulting solid waspurified by column chromatography (10 g of silica gel) with 1:1isopropyl ether/light petroleum ether as the eluting solvent. Theappropriate fraction was recrystallized from isopropyl ether and driedunder high vacuum to give the title compound, mp. 77.5°-80° C.

Analysis: Calculated for C₉ H₁₀ N₃ O₄ Cl: C, 41.63; H, 3.88, N, 16.18.Found: C, 41.61; H, 3.85; N, 16.10.

PREPARATION 53N-[6-Chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester

A solution of N-(6-chloro-3-nitro-2-pyridinyl) glycine ethyl ester (5.0g, 0.0193 mole) in tetrahydrofuran (100 ml) was hydrogenated overplatinum dioxide (0.5 g) at room temperature. After 2/3 of thetheoretical amount of hydrogen had been absorbed, the mixture wasfiltered and a fresh portion of platinum dioxide (0.5 g) was added. Thehydrogenation was continued until the theoretical amount of hydrogen wasabsorbed. The reaction mixture was cooled in ice, dried over magnesiumsulfate and filtered. Triethylamine (2.05 g, 0.0203 mole) and4-chlorobenzoyl chloride (3.55 g, 0.0203 mole) were addedsimultaneously, dropwise, to the cooled and stirred solution. Afterstirring at room temperature for 1.75 hours, the mixture was evaporatedunder reduced pressure and partitioned between water (100 ml) and ethylacetate (100 ml). The layers were separated and the aqueous layer wasre-extracted with ethyl acetate. The combined ethyl acetate layers werewashed three times with saturated sodium chloride solution, dried overmagnesium sulfate, charcoaled, filtered, and evaporated under reducedpressure. The resulting solid was dissolved in hot isopropyl alcohol,filtered hot and cooled to room temperature to give a solid which wascollected by filtration and rinsed with isopropyl ether to give 2.2 g oftitle compound (31% yield). A 0.5 g portion was dissolved in hotisopropyl alcohol, filtered hot, isopropyl ether was added, and themixture was cooled. The resulting suspension was filtered, the filtratewas evaporated under reduced pressure, and the residue wasrecrystallized from isopropyl alcohol/water and dried under high vacuumat 60° C. to give 0.37 g of the title compound, mp 157°-158.5° C.

Analysis: Calculated for C₁₆ H₁₅ N₃ O₃ Cl₂ : C, 52.19; H, 4.11, N,11.41. Found: C, 52.28; H, 4.05; N, 11.09.

EXAMPLE 1 2-(4-Chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid

A mixture of 2-(4-chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid ethyl ester (1.6 g, 0.005 mole), and crushed sodium hydroxide (0.2g, 0.005 mole) in aqueous ethanol (5 ml water and 4 ml ethanol) washeated at reflux for 1/2 hr. The reaction mixture was diluted with water(10 ml) and extracted with ether (2×). The aqueous layer was acidifiedwith 3N hydrochloric acid. The precipitate was collected, washed withwater, and dried under high vacuum at 50° C. overnight to give 0.84 g ofcrystals, mp 218°-20° C. with decomposition.

Analysis: Calculated for C₁₃ H₉ N₄ O₂ Cl: C, 54.09, H, 3.14, N, 19.41.Found: C, 53.94; H, 3.23; N, 19.09.

EXAMPLE 2 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A mixture of 14.6 g (0.04 mole) of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester,2.9 g (0.073 mole) of sodium hydroxide pellets, and 150 ml ofethanol/water (1:1) was refluxed for 45 min. The reaction mixture waspoured into a 250-ml of water, acidified with concentrated hydrochloricacid; and filtered, giving 12.8 g (97%) of a white solid. A 2-g portionwas recrystallized from methanol-water to give 1.2 g of white needles,mp 271°-273° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ Cl: C, 58.45; H, 3.50; N, 14.61.Found: C, 58.30; H, 3.50; N, 14.57.

EXAMPLE 3 2-(2-Chlorophenyl)-3-H-imidazo[4,5-b]pyridine-3-acetic acid.

A mixture of 9.7 g (0.0308 mole) of2-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester,2.5 g (0.0339 mole) of sodium hydroxide (pellets), and 100 ml ofethanol-water (1:1) was refluxed for 1 hr. The ethanol was evaporatedand the residual aqueous solution was extracted with methylene chloride(2×30 ml). The aqueous layer was acidified with concentratedhydrochloric acid and filtered. The filter cake was recrystallized fromethanol-water to give 7.0 g (79%). A 2.0-g portion was recrystallizedfrom ethanol-isopropyl ether to give white needles, mp 227°-228° C.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ Cl: C, 58.45; H, 3.50; N, 14.61.Found: C, 58.55; H, 3.54; N, 14.54.

EXAMPLE 4 2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A mixture of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3acetic acidethyl ester (6.0 g, 0.019 mole), sodium hydroxide pellets (0.9 g, 0.023mole), and 50 ml of ethanol-water (2:1) was refluxed for 1 hour. Thereaction mixture was cooled and the ethanol evaporated in vacuo. Theresidual aqueous mixture was diluted with water (40 ml) and extractedwith diethyl ether (2×25 ml). The aqueous portion was acidified withconcentrated hydrochloric acid to a pH of 5-6. After precipitation wascomplete, the solid was collected by filtration, giving 5.9 g (100%).Recrystallization from ethanol gave 4.7 g of cream colored needles, mp214°-216° C.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ Cl: C, 58.45; H, 3.50; N, 14.61.Found: C, 58.25; H, 3.51; N, 14.55.

EXAMPLE 5 2-(3-Fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A mixture of N-[3-[(3-fluorobenzoyl)amino]-2-pyridinyl] glycine ethylester (20.44 g, 0.065 mole), and ethylene glycol (75 ml) was heated at195° C. for 40 minutes. Water was added to the cooled reaction mixtureand the solid was collected by filtration. The solid was suspended inwater (2×100 ml) and collected by filtration to give 17.75 g of crude2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester.A portion of this solid (6.0 g, 0.02 mole) together with sodiumhydroxide pellets (0.9 g, 0.0231 mole), and 50 ml of ethanol-water (1:1)was refluxed for 1 hour. The ethanol was evaporated. The residualaqueous mixture was cooled, diluted with water (50 ml) and extractedwith diethyl ether (2×25 ml). The aqueous portion was acidified to a pHof 3 with concentrated hydrochloric acid. After precipitation wascomplete, the solid was collected by filtration. The filter cake wassuspended in ethanol and filtered, giving 4.94 g (91%).Recrystallization of a 1.2-g sample from tetrahydrofuran gave 1.1 g ofan off-white solid, mp 243°-245° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ F: C, 61.99; H, 3.72; N, 15.49.Found: C, 61.95; H, 3.73; N, 15.44.

EXAMPLE 6 2-(4-Bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester (7.00 g, 0.0194 mole) sodium hydroxide pellets (0.88 g,0.0220 mole), and 95% ethanol (100 ml) was refluxed for 1 hr. Thereaction mixture was cooled and filtered. The filter cake (7.3 g) wasdissolved in warm water, acidified with concentrated hydrochloric acid,and chilled. The precipitated solid was collected by filtration and thefilter cake was rinsed with water, giving 5.6 g (87%) of crystals.Recrystallization from tetrahydrofuran-methanol gave 5.4 g of whiteneedles, mp 264°-267° C.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ Br: C, 50.63; H, 3.03; N, 12.65.Found: C, 50.38; H, 2.97; N, 12.70.

EXAMPLE 7 2-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A solution of N-[3-[(4-fluorobenzoyl)amino]-2-pyridinyl] glycine ethylester (70.0 g, 0.2205 mole) in ethylene glycol was refluxed for 2 hours,cooled and 14% of the solution was removed. To the remaining solution(0.19 mole) was added 88 ml of water and solid potassium hydroxidepellets (21.4 g, 0.38 mole). The solution was heated at reflux for anadditional 11/4 hours, filtered into ice water (2 liter) and acidifiedwith 3N hydrochloric acid. The resulting solid was collected byfiltration, washed with water and dried under high vacuum at 60° C.overnight to give 45.5 g of crude title compound (88% yield). A 3.5-gportion of the solid was dissolved in hot methanol and filtered whilehot, and water was added to the cloud point. Upon cooling to roomtemperature, solid precipitated which was collected and recrystallizedagain from methanol/water to give 2.00 g of title compound after dryingunder high vacuum at 50° C., mp >250° C.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ F: C, 61.99; H, 3.72; N, 15.49.Found: C, 61.83; H, 3.71; N, 15.39.

EXAMPLE 8 2-(3-Bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A solution of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester (4.8 g, 0.0133 mole), 95% ethanol (50 ml), sodium hydroxidepellets (0.6 g, 0.014 mole), and water (5 ml) was refluxed for 2 hrs.The ethanol was evaporated and water (50 ml) added. Glacial acetic acidwas added dropwise until precipitation began (pH neutral). Theprecipitated solid was collected by filtration and recrystallized fromethanol-tetrahydrofuran, giving 3.9 g (88% yield) of white needles, mp247°-249° C.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ Br: C, 50.63; H, 3.03; N, 12.65.Found: C, 50.70; H, 3.02; N, 12.80.

EXAMPLE 9 2-(2-Pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A solution of 2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester (18.0 g, 0.064 mole), potassium hydroxide pellets (5.6 g,0.100 mole), 95% ethanol (250 ml) and water (10 ml) was refluxed for11/2 hr. The solution was evaporated to 1/3 volume and then diluted withwater (50 ml) and acidified with glacial acetic acid. Water (200 ml) wasadded and the mixture filtered after precipitation was complete, giving15.5 g (96%) of a granular solid. Recrystallization of a 2.0-g portiontwice from ethanol-water gave 1.5 g of an off-white granular solid, mp224°-225° C. with decomposition.

Analysis: Calculated for C₁₃ H₁₀ N₄ O₂ : C, 61.41; H, 3.96; N, 22.04.Found: C, 61.28; H, 3.94; N, 21.98.

EXAMPLE 102-[3-Trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid

A mixture of N-[3-[[3-(trifluoromethyl)benzoyl]amino]-22-pyridinyl]glycine ethyl ester (22.0 g, 0.06 mole) and ethylene glycol(100 ml) was heated at reflux for 40 minutes. The reaction mixture waspoured into water (300 ml) and cooled. The solid was collected byfiltration, washed with water (200 ml), and dried. The solid wasrecrystallized from isopropyl ether/tetrahydrofuran to give in 2 crops18.4 g (0.053 mole) of crude2-(3-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester. This solid together with potassium hydroxide pellets (4.7g, 0.084 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for21/2 hrs. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was dissolved in water (100 ml) andextracted with methylene chloride (2×30 ml). The aqueous portion wasacidified with glacial acetic acid and filtered after precipitation wascomplete. The filter cake was suspended in water (200 ml) and filtered.Recrystallization from tetrahydrofuran-isopropyl ether gave 15.3 g(91%). A 1.6-g sample was recrystallized from tetrahydrofuranisopropylether to give 1.0 g of an off-white solid, mp 240°-241.5° C.

Analysis: Calculated for C₁₅ H₁₀ N₃ O₂ F₃ : C, 56.08; H, 3.12; N, 13.08.Found: C, 55.72; H, 3.16; N, 12.76.

EXAMPLE 112-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid

A solution of 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (17.7 g, 0.051 mole), potassiumhydroxide pellets (4.5 g, 0.080 mole), 95% ethanol (150 ml), and water(10 ml) was refluxed for 21/2 hrs. The ethanol was evaporated in vacuo,the residue acidified with glacial acetic acid, and the mixturefiltered. The filter cake was suspended in water (300 ml) and filtered.The filter cake was air dried (17 g) and recrystallized fromethanol-water to give 12.21 g (75%) of a white solid, mp 240°-241° C.

Analysis: Calculated for C₁₅ H₁₀ N₃ O₂ F₃ : C, 56.08; H, 3.14; N, 13.08.Found: C, 56.02; H, 3.11; N, 13.07.

EXAMPLE 12 2-(3,4-Dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid

A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl] glycineethyl ester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heatedat reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40ml of water was added and the reaction mixture was heated at reflux for1 hr. The solution was filtered to remove yellow insoluble precipitate,the filtrate was diluted with 650 ml of water, and acidified withethanolic hydrogen chloride. The solid, which formed, was collected byfiltration, washed with water, and dried under high vacuum first at 50°C. overnight, then at 70° C. for 21/2 days to give 25.3 g (98%), mp248°-49° C.

Analysis: Calculated for C₁₄ H₉ N₃ O₂ Cl₂ : C, 52.20; H, 2.82; N, 13.04.Found: C, 52.15; H, 2.85; N, 12.92.

EXAMPLE 13 2-(4-Methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A mixture of N-[3-[(4-methoxybenzoyl)amino]-2-pyridinyl] glycine ethylester (32 g, 0.1 mole) and 167 ml of ethylene glycol was heated atreflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 mlof water was added, and the reaction mixture was heated at reflux for 1hr. The solution was filtered to remove yellow precipitate, the filtratewas diluted with 650 ml of water, and acidified with 3N hydrochloricacid. The solid which formed, was collected by filtration, washed withwater, and dried under high vacuum at 50° C. overnight to give 25.5 g(90.1% yield). A 0.5-g sample was recrystallized from ethanol, collectedby filtration, washed with cold ethanol and water, and dried under highvacuum at 70° C. over 2 days to give 0.47 g of crystals, mp 260°-63° C.

Analysis: Calculated for C₁₅ H₁₃ N₃ O₃ : C, 63.60; H, 4.63; N, 14.83.Found: C, 63.52; H, 4.63; N, 14.74.

EXAMPLE 14 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid

3-[[3-[(4-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethylester, (142 g, 0.409 mole) was refluxed in ethylene glycol (725 ml)under a nitrogen atmosphere for 2 hr until a solution formed. Solidpotassium hydroxide (31.9 g, 0.57 mole) and water (125 ml) were added tothe hot solution and a solid precipitated. After the suspension wasrefluxed for an additional 1.5 hours, it was poured into ice water (2liters) and acidified with a 3N hydrochloric acid solution. The solidwas collected by filtration and dried under high vacuum at 70° C. togive 96.9 g of a solid. 'H NMR of the solid showed it to contain amixture of the titled product and2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine. The solid was trituratedin pyridine (500 ml) at room temperature and filtered to remove2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine. The solid was rinsed wellwith water. The filtrate and washings were evaporated at reducedpressure until an aqueous suspension was left. The solid was collectedby filtration and rinsed with water to give 45.5 g of solid (37% yield).A 2.0-g sample of the solid was dissolved in hot methanol and thesolution was filtered hot. Upon cooling to room temperature, solidprecipitated. The solid was collected by filtration and dried under highvacuum at room temperature to give 0.65 g of solid, mp 232°-234° C.

Analysis: Calculated for C₁₅ H₁₂ N₃ O₂ Cl: C, 59.71; H, 4.01; N, 13.93.Found: C, 59.44; H, 4.04; N, 14.05.

EXAMPLE 15 2-(4-Chlorophenyl)-1H-imidazo[4,5-b]pyridine-1-acetic acidhydrate [1:1]

A mixture of 2-(4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-1-acetic acidethyl ester (8.4 g, 0.027 mole) and potassium hydroxide (2.25 g, 0.04mole) in 95% ethanol (75 ml) and water (5 ml) was heated at reflux for2.5 hours. The mixture was evaporated to dryness. The residue wasdissolved in water and acidified with glacial acetic acid. Theprecipitate was collected by filtration, washed with water, and driedunder high vacuum overnight at 60° C. to give 7.4 g (95% yield). A 1.4-gsample was dissolved in ˜450 ml of boiling methanol, and the solutionwas treated with Florisil® and filtered. The filtrate was concentratedand diluted with water. A crystalline precipitate was collected byfiltration, washed with water, and dried under high vacuum at 60° C. for4 hours, then at room temperature over the weekend to give 0.16 g ofsolids, mp. 194°-96° C.

Analysis: Calculated for C₁₄ H₁₀ N₃ O₂ Cl H₂ O: C, 55.00; H, 3.96; N,13.74. Found: C, 54.95; H, 3.98; N, 13.45.

EXAMPLE 16 2-(4-Bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A solution of N-[3-[(5-bromo-2-furanylcarbonyl)amino]2-pyridinyl]glycineester (110 g, 0.30 mole) in ethylene glycol (510 ml) was refluxed undernitrogen for two hours. The solution was cooled to room temperature andwater (100 ml) and potassium hydroxide pellets (23.25 g, 0.41 mole) wasadded. The solution was refluxed for an additional 1.5 hours and thenfiltered, while hot, into ice water (2 liters). A 3N hydrochloric acidsolution was added until the suspension was acidic. After stirringovernight, the solid was collected by filtration and rinsed with water.Most of the wet material was dried at 56° C. overnight under high vacuumto give 79.5 g of crude material (82% yield). A portion (3.0 g of wetmaterial) was dissolved in hot methanol, filtered, and cooled to roomtemperature. Addition of water caused a solid to precipitate which wascollected by filtration, rinsed with water, and dried at high vacuum at56° C. to give 1.59 g of title compound, mp 229°-231° C.

Analysis: Calculated for C₁₂ H₈ N₃ O₃ Br: C, 44.74; H, 2.50; N, 13.04.Found: C, 44.83; H, 2.42; N, 12.92.

EXAMPLE 17 2-(4-Nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidhydrate [1:1]

Under a nitrogen atmosphere, a suspension ofN-[3-[(4-nitrobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (47.4 g,0.138 mole) in ethylene glycol (235 ml) was refluxed, with stirring for1.5 hr. A solution was formed during heating. The solution was cooledand water (41.5 ml) and potassium hydroxide pellets (10.6 g, 0.189 mole)were added. Solid precipitated, but upon heating, a solution was againformed. The solution was refluxed for 2 hr, cooled, and poured into 750ml of ice water. Upon acidification with a 3N hydrochloric acidsolution, a yellow solid precipitated. The solid was collected byfiltration and rinsed with water. The solid was dissolved in hotmethanol, filtered hot and cooled to room temperature. Addition of watercaused solid to precipitate. The solid was collected by filtration anddried under high vacuum to give 16.4 g of orange solid (40% yield). 1.0g of the solid was dissolved in hot methanol, and the solution wastreated with charcoal, filtered hot, and cooled to room temperature,causing a solid to precipitate. The solid was collected by filtration,rinsed with water and dried under high vacuum at room temperatureovernight to give 0.61 g of title compound, mp. 249°-251° C.

Analysis: Calculated for C₁₄ H₁₂ N₄ O₅ : C, 53.17; H, 3.82; N,17.71.Found: C, 52.86; H, 3.64; N, 17.49.

EXAMPLE 18(S)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid

A mixture of (S)-N-[3-[(4-chlorophenyl)amino]-2-pyridinyl]alanine ethylester (4.0 g, 0.016 mole), and ethylene glycol (20 ml) was heated atreflux for 11/2 hr. To the cooled reaction mixture was added water (4ml) and solid potassium hydroxide (0.9 g, 0.016 mole). The mixture wasrefluxed for 2.75 hours and then filtered into ice water (70 ml). Solidprecipitated upon acidification with concentrated hydrochloric acid. Thesolid was collected by filtration, rinsed with water, dissolved in hotmethanol and the solution was treated with magnesium sulfate andcharcoal while hot. The mixture was filtered while hot. Upon cooling toroom temperature, a solid formed, which was collected by filtration anddried under high vacuum to give 1.20 g of solid. The solid wasredissolved in hot methanol, and the solution was filtered hot, andcooled to room temperature which caused a solid to precipitate. Waterwas added and the solid was collected by filtration, rinsed with water,and dried under high vacuum at 50° C. to give the title compound, mp.226°-229° C.

Analysis: Calculated for C₁₅ H₁₂ N₃ O₂ Cl: C, 59.71; H, 4.01; N, 13.93.Found: C, 59.82; H, 3.98; N, 14.02.

EXAMPLE 19 2-Phenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester

N-[3-(benzoylamino)-2-pyridinyl]glycine ethyl ester, 10.32 g (0.034mole) in two divided portions was heated in glass in a Wood's metal bathat 190° C. under a flow of nitrogen, one portion for 15 min and theother for 7 min. The green glassy residues were dissolved in methylenechloride, combined, and stirred together with 90 g of Florisil® for 1hr. The mixture was filtered, and the filtrate evaporated to an oil,which crystallized. The solid was recrystallized from hexanes to give acrystalline solid, which was dried under high vacuum at room temperatureovernight to give 3.67 g (39%) of crystals, m.p. 93°-95° C.

Analysis: Calculated for C₁₆ H₁₅ N₃ O₂ : C, 68.31; H, 5.37; N, 14.94.Found: C, 68.40; H, 5.35; N, 14.88.

EXAMPLE 20 2-Phenyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A 7.62-g (0.028 mole) sample ofN-[2-[[(aminocarbonyl)methyl]amino]-3-pyridinyl]benzamide was heated inglass in a Wood's metal bath under a flow of nitrogen at 200° C. for 7minutes. The green solid residue was broken up with a glass rod inmethanol and the solid was filtered off. The filtrate was concentratedand the precipitate which formed, was separated by filtering twice. Thesolids were combined and recrystallized from boiling water to give 3.19g (45%) of white needles which were dried under high vacuum at roomtemperature overnight, mp. 226°-7° C.

Analysis: Calculated for C₁₄ H₁₂ N₄ O: C, 66.66; H, 4.79; N, 22.21.Found: C, 66.63; H, 4.75; N, 22.25.

EXAMPLE 21 2-(2-Pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

SolidN-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]-2-pyridinecarboxamide(5.14 g, 0.019 mole) was heated in glass at 210°-15° C. in a Wood'smetal bath while stirring with a glass rod for 41/2 minutes. The darkgreen residue was triturated with methylene chloride (125 ml) and theinsoluble material was filtered off. This green solid was dissolved in450 ml of methanol, treated with 0.9 g of charcoal, and filtered throughCelite. The yellow filtrate was concentrated on a rotary evaporator toproduce a yellow crystalline solid. The solid was filtered andrecrystallized from methanol (3 crops by progressive concentration). Thecrops were combined and recrystallized from methanol-water to produce aprecipitate which was collected and dried under high vacuum at roomtemperature overnight to give 2.26 g (47%) of pale-yellow crystals, mp275°-78° C.

Analysis: Calculated for C₁₃ H₁₁ N₅ O: C, 61.65; H, 4.38; N, 27.65.Found: C, 61.33; H, 4.30; N, 27.27.

EXAMPLE 22 2-(2-Pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethylester

Solid N-[3-[(2-pyridinylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester(21.9 g, 0.069 mole) was heated in glass at 210°-220° C. using a heatingmantle for 71/2 minutes. The residue was dissolved in methylenechloride, treated with 25.6 g of charcoal, and filtered through a Celitepad. The filtrate was evaporated to a dark residue, which was taken upin ethyl acetate and filtered to remove an insoluble brown solid. Theconcentrated ethyl acetate filtrate was applied to a silica gel column(400 g) and eluted with ethyl acetate. The appropriate fractions werecombined and evaporated to a solid, which was placed under high vacuumfor several hours. The solid residue (6.9 g) was recrystallized fromethanol-water and refrigerated overnight. The crystalline precipitatewas filtered, washed with water, and dried under high vacuum at roomtemperature overnight to give 6.34 g of title compound (31%), mp109°-111° C.

Analysis: Calculated for C₁₅ H₁₄ N₄ O₂ : C, 63.82; H, 5.00; N, 19.85.Found: C, 64.06; H, 5.00; N, 2026.

EXAMPLE 23 2-(4-Chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid ethyl ester

The cyclization was effected by heating 12.3 g (0.037 mole) ofN-[3-[[(4-chloro-2-pyridinyl)carbonyl]amino]-2-pyridinyl]glycine ethylester at 200°-210° C. (oil bath) for 15 minutes. The dark residue wasdissolved in methylene chloride and filtered. The filtrate was treatedwith Florisil®, filtered, and evaporated to an oil, which crystallizedupon standing. The solid was recrystallized from methanol-water, washedwith 50% aqueous methanol, and dried under high vacuum at 50° C.overnight to give 2.44 g (21%) of title compound, mp 99°-101° C.

Analysis: Calculated for C₁₅ H₁₃ N₄ O₂ Cl: C, 56.88; H, 4.14; N, 17.69.Found: C, 56.88; H, 4.13; N, 17.64.

EXAMPLE 24 2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

Solid N-[3-[(3-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester,12.84 g (0.038 mole) was heated in glass at 210°-20° C. in a Wood'smetal bath for 7 minutes. The residue was dissolved in methylenechloride, treated with charcoal, and filtered through a Celite pad. Theorange filtrate was treated with Florisil® to give a pink filtrate. Thefiltrate was evaporated to give a solid, which was recrystallized fromtetrahydrofuran-petroleum ether. The solid was collected, washed withpetroleum ether, and dried under high vacuum at 50° C. for 5 hours togive 5.3 g (44%) of title compound, mp 98°-99.8° C.

Analysis: Calculated for C₁₆ H₁₄ N₃ O₂ Cl: C, 60.86; H, 4.47; N, 13.31.Found: C, 60.92; H, 4.54; N, 13.24.

EXAMPLE 25 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

Solid N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester,15.5 g (0.04 mole) was heated in glass at 210°-20° C. in a Wood's metalbath for 8 minutes. The residue was dissolved in methylene chloride,treated with charcoal, and filtered through a Celite pad. The filtrate(red) was treated with Florisil® to give a colorless filtrate. Thefiltrate was evaporated to give a solid, which was recrystallized fromtetrahydrofuran-petroleum ether. The solid was collected, washed withpetroleum ether (along with a small amount of tetrahydrofuran), anddried under high vacuum at 50° C. overnight to give 7.0 g (48%) of titlecompound, mp 123°-24° C.

Analysis: Calculated for C₁₆ H₁₄ N₃ O₂ Cl: C, 60.86; H, 4.47; N, 13.31.Found: C, 60.91; H, 4.48; N, 13.34.

EXAMPLE 26 2-(4-Methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

Solid N-[3-[(4-methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester,12.8 g (0.039 mole) was heated in glass in a Wood's metal bath at210°-220° C. for 6 minutes. The residue was dissolved in methylenechloride, treated with charcoal, and filtered through a Celite pad. Thefiltrate (dark orange) was treated with Florisil® to give a pale orangefiltrate. The filtrate was evaporated to a solid, which wasrecrystallized from tetrahydrofuran-petroleum ether. The solid wascollected, washed with tetrahydrofuranpetroleum ether and dried underhigh vacuum at 50° C. overnight to give 3.58 g (29.5%) of titlecompound, mp 107°-8° C.

Analysis: Calculated for C₁₇ N₁₇ N₃ O₃ : C, 65.58; H, 5.50; N, 13.50.Found: C, 65.69; H, 5.53; N, 13.46.

EXAMPLE 27 2-(2-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

Solid N-[3-[(2-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester,15.0 g (0.045 mole) was heated in a Wood's metal bath at 210°-20° C. for9 minutes. The residue was dissolved in methylene chloride, treated withFlorisil® (90 g), and filtered. The filtrate was treated withdecolorizing charcoal and filtered through a Celite pad to give a yellowfiltrate. The filtrate was evaporated to an oil, which crystallized uponstanding. The solid (3.0 g) was recrystallized from petroleumether-tetrahydrofuran (minimum) by cooling in a freezer overnight. Thesolid was collected, washed with petroleum ether-tetrahydrofuran anddried under high vacuum at room temperature to give 1.62 g (11%) oftitle compound, mp 64°-66° C.

Analysis: Calculated for C₁₆ H₁₄ N₃ O₂ Cl: C, 60.86; H, 4.47; N, 13.30.Found: C, 61.07; H, 4.52; N, 13.30.

EXAMPLE 28 2-(2-Methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester hydrochloride [1:1]

Solid N-[3-[(2-methoxybenzoyl)amino]-2-pyridinyl]glycine ethyl ester,13.75 g (0.042 mole) was heated in glass in a Wood's metal bath at210°-20° C. for 2 minutes, then at 215°-20° C. for 2 minutes. Theresidue was dissolved in methylene chloride, treated with activatedcharcoal, and filtered through a Celite pad. The filtrate (dark orange)was treated with Florisil® to give a dark filtrate, which was evaporatedto give an oil. The oil was dissolved in isopropyl alcohol, filtered andthe filtrate acidified with methanolic hydrogen chloride and dilutedwith isopropyl ether. The crystalline crop was collected, washed withisopropyl etherisopropyl alcohol (minimum), and dried under high vacuumat room temperature overnight to give 1.6 g (11%) of title compound, mp177°-80° C.

Analysis: Calculated for C₁₇ H₁₈ N₃ O₃ Cl: C, 58.71; H, 5.22; N, 12.08.Found: C, 58.64; H, 5.24; N, 12.06.

EXAMPLE 292-(4-Chloro-2-pyridinyl)-3-[2-(4-methyl-2-piperazinyl)-2-oxoethyl]-3H-imidazo[4,5-b]pyridine

A solution of ethyl chloroformate (0.66 g, 0.0061 mole) in 20 ml ofmethylene chloride was added slowly to a solution of2-(4-chloro-2-pyridinyl)-3H-imidazo[4,5-b]pyridine acetic acid (1.75 g,0.006 mole) and triethylamine (0.68 g, 0.0067 mole) in 75 ml ofmethylene chloride. After the solution was allowed to stir at roomtemperature for 2 hrs, a solution of N-methylpiperazine (0.61 g, 0.0061mole) in methylene chloride was added slowly at room temperature andallowed to stir overnight. The reaction mixture was filtered and thefiltrate was evaporated to dryness. The residue was partitioned betweendilute hydrochloric acid and diethyl ether. The aqueous layer wasseparated and extracted with diethyl ester (2×) and methylene chloride(3×). The aqueous layer was neutralized (pH 7) and refrigerated. Thesmall amount of precipitate was removed by filtration. The aqueousfiltrate was basified and extracted with methylene chloride (3×). Themethylene chloride extracts were combined and evaporated to a gum. Thegummy residue was purified by alumina column chromatography (Brockmanactivity 1, 80-200 mesh, 40 g) by elution with 20% acetone/80% benzene.The appropriate fractions (TLC) were combined and evaporated. Theresidue was crystallized from acetone/petroleum ether (bp 50°-110° C.).The crystalline solid was collected, washed with petroleum ether andisopropyl ether, and dried under high vacuum at room temperature to give0.54 g (24%) of title compound, mp 174°-75° C.

Analysis: Calculated for C₁₈ H₁₉ N₆ OCl: C, 58.30; H, 5.16; N, 22.66.Found: C, 58.29; H, 5.21; N, 22.53.

EXAMPLE 30 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture ofN-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]4-chlorobenzamide (6.0 g,0.03 mole) in 150 ml of ethylene glycol was heated at 190° C. for 40minutes. The precipitate, which formed, was filtered off and washed withwater. The filtrate was diluted with water to produce a second crop. Thefirst crop was heated to boiling in 300 ml of methanol, filtered througha Celite pad, seeded, and refrigerated overnight. The crystallineprecipitate was filtered, washed with cold methanol, and dried underhigh vacuum at 60° C. overnight to give 1.42 g (25%) of title compound,mp 270°-1° C.

Analysis: Calculated for C₁₄ H₁₁ N₄ OCl: C, 58.65; H, 3.87; N, 19.54.Found: C, 58.38; H, 3.86; N, 19.56.

EXAMPLE 31 2-(2-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:1]

The solid N-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]2-chlorobenzamide(7.1 g, 0.023 mole) was heated in glass at 210° C. in a Wood's metalbath for 6 min. The residue was dissolved in methanol (800 ml) andtreated with 5.25 g of charcoal. The mixture was filtered through Celiteand the filtrate was evaporated to dryness to give 6.3 g residue (85%)crude yield). A 2-g sample was dissolved in 150 ml of ethyl acetate andfiltered. The filtrate was acidified with ethereal hydrogen chloride toproduce a gummy precipitate which was solubilized by the addition ofmethanolic hydrogen chloride. The crystalline precipitate, which formed,was filtered, washed with acetonitrile, and dried under high vacuum atroom temperature overnight. The solid was recrystallized from methanol(minimum)/ethyl acetate to give a pale yellow solid which was driedunder high vacuum at room temperature over the weekend to give 1.2 g oftitle compound, mp 250°-55° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₁ N₄ OCl.HCl: C, 52.03; H, 3.74; N,17.33. Found: C, 51.77; H, 3.75; N, 17.02.

EXAMPLE 322-(3-Chlorophenyl)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]3H-imidazo[4,5-b]pyridinefumarate [2:3]

A stream of nitrogen gas was bubbled through a stirred solution of2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.68 g,0.0128 mole), 1,1'-carbonyldiimidazole (2.07 g, 0.0128 mole), andanhydrous tetrahydrofuram (70 ml) for 21/2 hrs. at room temperature. Asolution of N-methylpiperazine in 10 ml of tetrahydrofuran was added(rapid drop) and stirring was continued for 4 hrs. at room temperature.The tetrahydrofuran was evaporated and the residue was dissolved inmethylene chloride (75 ml). The methylene chloride solution was washedwith water (2×30 ml), dried over sodium sulfate, and concentrated invacuo. The residue was converted to the sesquifumarate salt andcrystallized from isopropyl alcohol-isopropyl ether. Recrystallizationtwice from isopropyl alcohol-isopropyl ether gave 3.2 g (46%) of a whitesolid, mp 190°-193° C. with decomposition.

Analysis: Calculated for C₂₅ H₂₆ N₅ O₇ Cl: C, 55.20; H, 4.82; N, 12.87.Found: C, 55.44; H, 4.96; N, 13.23.

EXAMPLE 332-(3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]3H-imidazo[4,5-b]pyridine,fumarate [2:3]

A stream of nitrogen gas was bubbled through a stirred suspension of2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g,0.0151 mole), 1,1'-carbonyldiimidazole (2.5 g, 0.0151 mole) andanhydrous tetrahydrofuran (100 ml) for 2 hrs. at room temperature. Asolution of N-methylpiperazine (1.5 g, 0.0151 mole) in tetrahydrofuran(5 ml) was added dropwise, and the reaction solution was stirred 31/2hrs at room temperature. The tetrahydrofuran was evaporated and theresidue dissolved in 75 ml of methylene chloride. The methylene chloridesolution was washed with water (2×20 ml), dried over sodium sulfate, andconcentrated in vacuo. The residue was converted to the sesquifumaratesalt and crystallized from isopropyl alcohol-isopropyl ether.Recrystallization twice from isopropyl alcohol-isopropyl ether gave 5.2g (22%) of white solid, mp 183°-185° C.

Analysis: Calculated for C₂₅ H₂₆ N₅ O₇ F: C, 56.92; H, 4.97; N, 13.28Found: C, 57.20; H, 5.08; N, 13.61

EXAMPLE 342-(4-Fluorophenyl)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]3H-imidazo[4,5-b]pyridine,fumarate [1:1]

A stream of nitrogen gas was bubbled through a stirred suspension of2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.6 g,0.0133 mole), 1,1'-carbonyldiimidazole (2.2 g, 0.133 mole) and anhydroustetrahydrofuran (50 ml) for 3 hrs. at room temperature. A solution ofN-methylpiperazine (1.3 g, 0.133 mole) in 10 ml of tetrahydrofuran wasadded dropwise and the solution was stirred for 18 hrs. at roomtemperature. The tetrahydrofuran was evaporated and the residue wasdissolved in methylene chloride (75 ml). The methylene chloride solutionwas washed with water (3×25 ml), dried over sodium sulfate, andconcentrated in vacuo. The residue was converted to the fumarate saltand crystallized from isopropyl alcohol-isopropyl ether, giving 5.3 g(85%). Recrystallization from isopropyl alcohol-isopropyl ether gave 5.1g of white solid, mp 187°-188.5° C.

Analysis: Calculated for C₂₃ H₂₄ N₅ O₅ F: C, 58.84; H, 5.15; N, 14.92.Found: C, 58.49; H, 5.23; N, 14.75.

EXAMPLE 352-(4-Chlorophenyl)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]3H-imidazo[4,5-b]pyridine,fumarate [1:1]

A stream of nitrogen gas was bubbled through a stirred suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.32 g,0.0081 mole), 1,1'-carbonyldiimidazole (1.31 g, 0.0081 mole) andanhydrous tetrahydrofuran (50 ml) for 3 hrs. at room temperature. Asolution of N-methylpiperazine (0.81 g, 0.0081 mole) in 10 ml oftetrahydrofuran was added and the solution was stirred at roomtemperature overnight. The tetrahydrofuran was evaporated and theresidue was dissolved in methylene chloride (75 ml). The methylenechloride solution was washed with water (3×25 ml), dried over sodiumsulfate and concentrated in vacuo. The residue was converted to thefumarate salt and crystallized from isopropyl alcohol-isopropyl ether,to give 3.52 g (89%) slightly impure title compound. Recrystallizationfrom isopropyl alcohol-isopropyl ether gave 2.5 g of title compound,white solid, mp 190°-196° C.

Analysis: Calculated for C₂₃ H₂₄ N₅ O₅ Cl: C, 56.85; H, 4.98; N, 14.41.Found: C, 57.10; H, 5.24; N, 14.35.

EXAMPLE 362-(4-Bromophenyl)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-3H-imidazo[4,5-b]pyridinefumarate [1:1]

A suspension of 4.4 g (0.0133 mole) of2-(4-bromophenyl)3H-imidazo[4,5-b]pyridine-3-acetic acid, 2.2 g (0.0133mole) of 1,1'-carbonyldiimidazole, and anhydrous tetrahydrofuran (100ml) was stirred at room temperature with a stream of nitrogen bubblingthrough the mixture for 3 hours. To the resulting solution was addeddropwise a solution of 1.3 g (0.0133 mole) of N-methylpiperazine in 10ml of tetrahydrofuran. The reaction mixture was stirred at roomtemperature for 18 hours. The tetrahydrofuran was evaporated and theresidue taken up in methylene chloride (75 ml) was washed with water(3×25 ml). The methylene chloride solution was dried over sodium sulfateand concentrated in vacuo. The residue was converted to the fumaratesalt and crystallized from ethanol-ethyl acetate, giving 6.5 g.Recrystallization from ethanol-ethyl acetate and then from isopropylalcohol-isopropyl ether gave 3.2 g (45%) of white solid, mp 203°-203.5°C. with decomposition.

Analysis: Calculated for C₂₃ H₂₄ N₅ O₅ Br: C, 52.09; H, 4.56; N, 13.20.Found: C, 51.91; H, 4.62; N, 13.26.

EXAMPLE 37 2-(3-Chlorophenyl)-3H-imidazo[r,t-b]pyridine-3-acetamide

A suspension ofN-[2-[(2-amino-2-oxoethyl)amino]-3-pyridinyl]3-chlorobenzamide (8.7 g,0.029 mole) in 200 ml of ethylene glycol was heated at 190° C. for 40minutes. The reaction mixture was allowed to cool to room temperatureand filtered. The filtrate was diluted with water to produce a whiteprecipitate. The mixture was refrigerated and the precipitate wasfiltered, washed with water, and dried under high vacuum at roomtemperature overnight, then at 60° C. for 6 hrs. The sample wasrecrystallized from methanol-water (˜40/60-) and refrigerated. Thecrystalline precipitate was filtered, washed with water, and dried underhigh vacuum at room temperature overnight. The sample was redried underhigh vacuum at 60° C. overnight to give 5.48 g (66%) of title compound,mp. 245°-47° C.

Analysis: Calculated for C₁₄ H₁₁ N₄ OCl: C, 58.65; H, 3.87; N, 19.54.Found: C, 58.44; H, 3.86; N, 19.56.

EXAMPLE 38 2-(4-Chlorophenyl)-3H-imidazo[4,5-pyridine-3-propanoic acidethyl ester

Solid 3-[[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acidethyl ester, (14.5 g, 0.042 mole) was heated in glass at 202°-205° C. ina Woods metal bath for 51/4 minutes. The residue was purified on asilica gel column (400 g) by elution with 5% methanol/95% toluene. Theappropriate frictions were pooled and evaporated to an oil whichcrystallized upon standing (10.7 g). A 3-g sample was recrystallizedfrom methanol-water. The solid was filtered, washed with water, anddried under high vacuum at room temperature overnight to give 1.45 g(˜37%) of title compound, mp 57°-59° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₂ Cl: C, 61.91; H, 4.89; N, 12.74.Found: C, 62.07; H, 4.92; N, 12.88.

EXAMPLE 39 2-(3-Bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

A solution of 0.080 mole of 3-bromobenzoyl chloride (freshly prepared)in 30 -ml methylene chloride was added dropwise to a stirred and chilled(10°-15° C.) solution of 14.4 g (0.075 mole) ofN-[[3-amino]-2-pyridinyl]glycine ethyl ester in dry tetrahydrofuran (100ml) and dry methylene chloride (100 ml) while adding simultaneously(dropwise) a solution of 8.1 g, (0.080 mole) of triethylamine andmethylene chloride (30 ml). The reaction mixture was stirred for 16 hrsat room temperature. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in methylene chloride(250 ml) and washed with water (50 ml), 5% aqueous sodium hydroxidesolution (2×50 ml) water (2×50 ml), dried over sodium sulfate, andconcentrated in vacuo.

The residue (21 g) was dissolved in ethanol and heated on a hot plate torecrystallize. The ethanol evaporated, and continued heating for anundetermined length of time effected cyclodehydration. The melt wascooled and dissolved in methylene chloride (200 ml) and the solutiontreated with Florisil®. The mixture was filtered, rising the Florisil®with a mixture of methylene chloride-tetrahydrofuram. The filtrate wasconcentrated in vacuo and the residue recrystallized from isopropylalcohol-isopropyl ether, giving 6.6 g (24%). A 1.6-g sample wasdissolved in methylene chloride and again treated with Florisil®. Themixture was filtered and the filtrate concentrated in vacuo. The residuewas recrystallized from isopropyl alcohol-isopropyl ether to give 1.0 gof a white solid, mp 87°-90° C.

Analysis: Calculated for C₁₆ H₁₄ N₃ O₂ Br: C, 53.35; H, 3.92; N, 11.67.Found: C, 53.60; H, 3.94; N, 11.92.

EXAMPLE 402-(4-Chlorophenyl)-3-[4-morpholinyl)-2-oxoethyl]-3H-imidazo[4,5-b]pyridine

A stream of nitrogen gas was bubbled through a stirred suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.96 g,0.0208 mole), 1,1'-carbonyldiimidazole (3.37 g, 0.0208 mole), andanhydrous tetrahydrofuran (100 ml) at room temperature for 3 hrs. To theresulting solution was added dropwise a solution of morpholine (1.81 g,0.0208 mole) in tetrahydrofuran (10 ml). The reaction mixture wasstirred overnight at room temperature. The tetrahydrofuran wasevaporated and the crystalline residue suspended in water and filtered,giving 5.35 g (72%). Recrystallization from 95% ethanol gave 4.9 g ofwhite flakes, mp 213°-216° C.

Analysis: Calculated for C₁₈ H₁₇ N₄ O₂ Cl: C, 60.59; H, 4.80; N, 15.70.Found: C, 60.84; H, 4.84; N, 15.94.

EXAMPLE 412-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A stream of nitrogen was bubbled through a stirred suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-pyridine-3-acetic acid (4.50 g, 0.0157mole), 1,1'-carbonyldiimidazole (2.54 g, 0.0157 mole) and anhydrousmethylene chloride (100 ml) for 2 hrs at room temperature. A solution ofN,N-dimethylethylenediamine (1.50 g, 0.0170 mole) in 10 ml of methylenechloride was added dropwise and the reaction mixture was stirredovernight at room temperature. The methylene chloride was washed withwater (2×30 ml), 5% sodium hydroxide (2×30 ml), water (30 ml), driedover sodium sulfate and concentrated. The residue (4.5 g) wasrecrystallized from isopropyl alcohol to give 3.5 g (62%) of whiteflakes, mp 195°-196.5° C.

Analysis: Calculated for C₁₈ H₂₀ N₅ OCl: C, 60.42; H, 5.63; N, 19.57.Found: C, 60.57; H, 5.68; N, 19.87.

EXAMPLE 422-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride [1:2]

2-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide(0.5 g, 0.0014 mole) was dissolved in acetone, acidified with ethanolichydrogen chloride, and seeded to initiate crystallization. The solid wascollected by filtration, washed with diethyl ether, and dried under highvacuum at room temperature overnight to give 0.60 g (quantitativeyield), m.p. 222°-25° C.

Analysis: Calculated for C₁₈ H₂₂ N₅ OCl₂ : C, 50.19; H, 5.15; N, 16.26.Found: C, 50.00; H, 5.25; N, 16.16.

EXAMPLE 432-(4-Chlorophenyl)-N-(3-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

Under a nitrogen atmosphere, oxalyl chloride (2.41 g, 0.0190 mole) wasadded dropwise to a stirred suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.28 g,0.0184 mole) in anhydrous dimethylformamide (70 ml). The resultingsolution was stirred at room temperature for 3 hrs and was then addeddropwise to a stirred and chilled (15°-20° C.) solution of3-aminopyridine (1.79 , 0.0190 mole), triethylamine (1.92 , 0.0190 mole)and dimethylformamide (30 ml). The reaction mixture was stirred at roomtemperature overnight and then poured into 300 ml of water. The mixturewas filtered. The filter cake was suspended between methylene chloride(200 ml) and 5% sodium hydroxide (100 ml) and the methylene chloride wasseparated. The aqueous portion was extracted with methylene chloride(100 ml). The combined methylene chloride layers were washed with 5%sodium hydroxide (2×50 ml), water (50 ml), dried over sodium sulfate,and concentrated. The residue (4.3 g, 66%) was twice recrystallized fromisopropyl alcohol-isopropyl ether to give 3.2 g of a white granularsolid, mp 217°-218° C.

Analysis: Calculated for C₁₉ H₁₅ N₅ O₁.5 Cl: C, 61.21; H, 4.06; N,18.78. Found: C, 60.93; H, 4.11; N, 19.04.

EXAMPLE 442-(4-Chlorophenyl)-N-(3-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:1.5]

Solid2-(4-chlorophenyl)-N-(3-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide(0.50 g) was dissolved in isopropyl alcohol and acidified with excessethereal hydrogen chloride to produce a crystalline precipitate. Thesolid was collected, washed with ether, and dried under high vacuum atroom temperature overnight to give 0.58 g (91%), mp 189°-91° C.

Analysis: Calculated for C₁₉ H₁₉ N₅ O₂.5 Cl₃ : C, 49.21; H, 4.13; N,15.10. Found: C, 49.20; H, 4.06; N, 15.07.

EXAMPLE 452-(3-Bromophenyl)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-3H-imidazo[4,5-b]pyridinefumarate [2:3]

A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (3.00 g, 0.0090 mole), 1,1'-carbonyldiimidazole (1.46 g, 0.0090mole) and anhydrous tetrahydrofuran (50 ml) was stirred at roomtemperature with a stream of nitrogen bubbling through the mixture for 3hrs. A solution of N-methylpiperazine (0.90 g, 0.0090 mole) in 10 ml oftetrahydrofuran (dry) was added and stirring continued at roomtemperature overnight. The tetrahydrofuran was evaporated and theresidue dissolved in methylene chloride (50 ml) and washed with water(3×25 ml), dried over sodium sulfate, and concentrated in vacuo. Theresidue (3.0 g) was converted to the 11/2 fumarate salt andrecrystallized twice from isopropyl alcohol-isopropyl ether, giving 2.36g (45%) of an off-white granular solid, mp 192°-194° C. withdecomposition.

Analysis: Calculated for C₂₅ H₂₆ N₅ O₇ Br: C, 51.03; H, 4.45; N, 11.90.Found: C, 51.01; H, 4.46; N, 12.11.

EXAMPLE 462-(4-Chlorophenyl)-3-[2-oxo-2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]-3H-imidazo[4,5-b]pyridine

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (4.0 g, 0.014 mole), 1,1'-carbonyldiimidazole (2.3 g, 0.014 mole),and anhydrous tetrahydrofuran (100 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through the mixture for 21/2 hrs. Asolution of N-(α, α, α-trifluoro-m-tolyl)-piperazine (3.2 g, 0.014 mole)in dry tetrahydrofuran (10 ml) was added and the reaction mixture wasstirred at room temperature for 41/2 hrs. The tetrahydrofuran wasevaporated and the residue dissolved in methylene chloride (75 ml). Themethylene chloride solution was extracted with 5% potassium hydroxidesolution (2×30 ml), water (30 ml), brine (25 ml), dried over sodiumsulfate, and concentrated in vacuo. The residue (6.6 g) was twicerecrystallized from isopropyl alcohol-isopropyl ether to give 3.3 g(47%) of white needles, mp 185°-186.5° C.

Analysis: Calculated for C₂₅ N₂₁ N₅ OClF₃ : C, 60.06; H, 4.24; N, 14.01.Found: C, 59.95; H, 4.16; N, 13.92.

EXAMPLE 472-(4-Chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, a suspension of2-(4-chlorophenyl)3H-imidazo[4,5-b]pyridine-3-acetic acid, 6.0 g (0.021mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) intetrahydrofuran (150 ml) was refluxed, with stirring, for 2.5 hrs. Themixture was cooled to room temperature and a solution of 3.6 g (0.116mole) of monomethylamine in tetrahydrofuran (60 ml) was added dropwiseand the reaction mixture was stirred in room temperature overnight. Thetetrahydrofuran was evaporated and the residue was triturated in water(150 ml). The solid was filtered and rinsed with water. The solid wasdissolved in hot isopropyl alcohol, treated with charcoal, filtered, andallowed to cool. Solid formed, and water was added to precipitate more.The solid was filtered and dried under vacuum to give 3.0 g (47.5%) oftitle compound, mp 238°-238.5° C.

Analysis: Calculated for C₁₅ H₁₃ N₄ OCl: C, 59.91; H, 4.36; N, 18.63.Found: C, 59.76; H, 4.37; N, 18.43.

EXAMPLE 482-(4-Chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (3.0 g, 0.010 mole) 1,1'-carbonyldiimidazole (1.7 g, 0.010 mole)and dry tetrahydrofuran (150 ml) was stirred for 3 hrs. at roomtemperature with a stream of nitrogen bubbling through it. A solution of1.0 g of dimethylamine in 25 ml of tetrahydrofuran was added and thereaction container was stoppered and the mixture was stirred overnightat room temperature. The tetrahydrofuran was evaporated and the residuetriturated in water (50 ml) and filtered. The filter cake wasrecrystallized from isopropyl alcohol and then from ethanol, giving 2.4g (32%) of white needles, mp 212°-213° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OCl: C, 61.05; H, 4.80; N, 17.80.Found: C, 60.78; H, 4.76; N, 17.67.

EXAMPLE 492-(4-Chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride[1:1]

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(6.0 g, 0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in150 ml of tetrahydrofuran was stirred at room temperature for 3 hourswith nitrogen bubbling through it. A solution of dimethylamine intetrahydrofuran (84 ml of 1M solution, 0.042 mole) was added dropwise atroom temperature to the stirred solution and the reaction mixture wasallowed to stir at room temperature overnight. The tetrahydrofuran wasevaporated and the solid was triturated with water. The solid wascollected and dried under high vacuum overnight. The solid was dissolvedin tetrahydrofuran and acidified with ethereal hydrogen chloride toproduce a crystalline precipitate, which was collected, washed withtetrahydrofuran, and dried under high vacuum overnight at roomtemperature to give 5.3 g, (73%), mp 216°-219.5° C.

Analysis: Calculated for C₁₆ H₁₆ N₄ OCl₂ : C, 54.71; H, 4.59; N, 15.95.Found: C, 54.58; H, 4.64; N, 15.88.

EXAMPLE 50 2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acidethyl ester hydrochloride[1:1]

N-[[3-[(3-Chlorobenzoyl)amino]-2-pyridinyl]amino]propanoic acid ethylester (17.3 g, 0.05 mole) was heated at 205° C. in glass in a Wood'smetal bath for 12-13 minutes. The residue was dissolved in ethylacetate, filtered to remove small amounts of insoluble material, andevaporated to dryness. The residue was purified on a silica gel column(400 g) by elution with 5% methanol/95% toluene. The appropriatefractions were combined and evaporated. Latter fractions containingproduct were treated with Florisil® to remove color. Total yield of freebase was 13.0 g (79%). A 2.5-g sample was dissolved in tetrahydrofuran,acidified with excess ethereal hydrogen chloride, and allowed to slowlycrystallize. The solid was collected, washed with anhydrous ether, anddried under high vacuum at room temperature overnight to give 2.45 g ofproduct in 2 crops, mp 144°-46° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₂ Cl HCl: C, 55.75; H, 4.68; N,11.47. Found: C, 55.84; H, 4.66; N, 11.44.

EXAMPLE 51 2-(2-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acidethyl ester hydrochloride[1:1]

3-[[3-[(2-Chlorobenzoyl)amino]-2-pyridinyl]-amino]propanoic acid ethylester (12.36 g, 0.036 mole) was heated at 220°-225° C. in glass in aWood's metal bath for 13 minutes. The residue was purified on a silicagel column (400 g) by elution with 5% methanol/95% toluene. Theappropriate fractions were combined and evaporated to an oil. Latterfractions containing product plus red color were treated with Florisil®to remove the color. Total yield of free base was 64%. A 2.1-g sample ofthe oil was dissolved in tetrahydrofuran, acidified with etherealhydrogen chloride, and allowed to slowly crystallize. The crystallineprecipitate was collected, washed with cold tetrahydrofuran and diethylether, and dried under high vacuum at room temperature overnight to give1.65 g, mp 173°-76° C.

Analysis: Calculated for C₁₇ N₁₆ N₃ O₂ Cl.HCl: C, 55.75; H, 4.68; N,11.47. Found: C, 55.66; H, 4.68; N, 11.38.

EXAMPLE 52 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid1,1-dimethyl ethyl ester

Under a nitrogen atmosphere, N,N-dimethylformamide-ditert-butyl acetal(8.0 g, 0.044 mole) was added dropwise over a 20-minute period to astirred and refluxing suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.11 g,0.011 mole) in dry benzene (50 ml). Refluxing was continued for 4 hrs.The cooled solution was washed with dilute sodium bicarbonate solution(3×25 ml), water (25 ml), dried over sodium sulfate, and concentrated invacuo. The residue, 3.6 g (24%) was twice recrystallized from isopropylether to give an off-white solid, mp 89°-92° C.

Analysis: Calculated for C₁₈ H₁₈ N₃ O₂ Cl: C, 62.88; H, 5.28; N, 12.22.Found: C, 62.91; H, 5.33; N, 12.36.

EXAMPLE 532-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-ethanethioamidehydrate[1:0.5]

A mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetamide(3.44 g, 0.012 mole) and phosphorus pentasulfide (1.47 g, 0.0033 mole)in 150 ml of dry acetonitrile (dried over molecular sieves) was heatedat reflux for 3 hr. The reaction mixture was filtered and washed withboiling acetonitrile. The solid residue in the flask was treated withboiling methanol and filtered. The methanol and acetonitrile filtrateswere combined and evaporated to dryness. The residue was treated withacetone and filtered through a silica gel filter funnel. The filtratewas treated with Florisil®, filtered, and evaporated to dryness. Theresidue was treated with acetone, applied to a silica gel column (7×15cm), and eluted with acetone. The appropriate fractions were combinedand evaporated. The residue was dissolved in hot methanol, treated withactivated charcoal, and filtered through a Celite pad. The filtrate wasconcentrated to initiate crystallization. The mixture was diluted withwater and ice, then filtered to collect the precipitate which was washedwith water. The solid was dried under high vacuum overnight at roomtemperature, then at 55° C. for 5 hr. to give 0.31 g product (8.3%), mp226°-29° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₁ SN₄ Cl.1/2H₂ O: C, 53.93; H, 3.88; N,17.97. Found: C, 54.26; H, 3.83; N, 17.68.

EXAMPLE 54 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidmethyl ester

A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid(3.1 g, 0.1011 mole), methanol (100 ml) and concentrated sulfuric acid(3 ml) was refluxed overnight under a Dean-Stark trap. Another 2 ml ofconcentrated sulfuric acid and methanol (50 ml) was added and refluxcontinued for 12 hr. The methanol was evaporated, water (50 ml) wasadded, and sodium bicarbonate (solid) added until basic. The mixture wasextracted with ethyl acetate (3×25 ml). The combined ethyl acetateextracts were washed with water (25 ml), dried over sodium sulfate, andconcentrated in vacuo. The residue (2.5 g) was combined with a sampleobtained previously and recrystallized from isopropyl ether-isopropylalcohol to give 3.0 g (56%) of white needles, mp 198°-200° C.

Analysis: Calculated for C₁₅ H₁₂ N₃ O₂ Cl: C, 59.71; H, 4.01; N, 13.93.Found: C, 59.64; H, 3.98; N, 13.85.

EXAMPLE 55 2-(4-Chlorophenyl)-3H-imidazol[4,5-b]pyridine-3-acetic acid1-methylethyl ester

A solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid(3.1 g, 0.0108 mole), isopropanol (50 ml), benzene (50 ml), andconcentrated sulfuric acid (5 ml) was refluxed under a Dean-Stark trapfor 24 hrs. The reaction mixture was concentrated and the residuepartitioned between 5% potassium hydroxide solution (50 ml) and ethylacetate (50 ml). The layers were separated and the aqueous portionextracted with ethyl acetate (2×25 ml). The organic layers were combinedand washed with 5% potassium hydroxide (25 ml), water (25 ml), driedover sodium sulfate, and concentrated in vacuo to give 2.0 g (56%) of asolid, mp 118°-120° C. Recrystallization from isopropyl ether gave 1.7 gof off-white needles, mp 117.5°-119° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₂ Cl: C, 61.92; H, 4.89; N, 12.74.Found: C, 61.87; H, 4.84; N, 12.67.

EXAMPLE 56 N,N-Dimethyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g, 0.031 mole),1,1'-carbonyldiimidazole (6.0 g, 0.037 mole), and dry tetrahydrofuran(200 ml) was stirred at room temperature for 2 hr. with a stream ofnitrogen bubbling through it. The suspension was heated at 50° C. undernitrogen for 2 hr, cooled in ice and treated with a solution ofdimethylamine in tetrahydrofuran (4.22 g of dimethylamine in 40 ml oftetrahydrofuran.) The solution was stirred at room temperatureovernight, more dimethylamine (0.071 mole in 30 ml of tetrahydrofuran)was added, and the reaction mixture was heated at 45° C. for 3 hr. Thereaction mixture was concentrated under reduced pressure; the resultingsolid was triturated in water, filtered, rinsed twice with water, twicewith 5% potassium hydroxide solution and then twice again with water.The solid was dissolved in hot isopropyl alcohol, filtered hot, andcooled. Water was added and the solid filtered and dried at 80° C. undervacuum to yield 3.55 g (33%) of white solid, mp. 181°-183° C.

Analysis: Calculated for C₁₇ H₁₅ N₄ OF₃ : C, 58.62; H, 4.32; N, 16.08.Found: C, 58.76; H, 4.37; N, 16.07.

EXAMPLE 573-[2-(4-Methyl-1-piperazinyl)-2-oxoethyl]-2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridinefumarate[1:1]

A solution of (2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(3.00 g, 0.012 mole), 1,1'-carbonyldiimidazole (1.94 g, 0.012 mole), andanhydrous tetrahydrofuran (50 ml) was stirred at room temperature with astream of nitrogen bubbling through it for 21/2 hours. The nitrogen flowwas stopped, N-methylpiperazine (1.2 g, 0.012 mole) added, and thereaction mixture was stoppered and stirred over the weekend. Thetetrahydrofuran was evaporated, water (100 ml) added, and the mixturebasified with 10% sodium hydroxide solution. The mixture was extractedwith ethyl acetate (4×25 ml). The combined organic extracts were washedwith water (25 ml), dried over sodium sulfate, and concentrated invacuo. The residue (1.3 g) was converted to the fumarate salt andcrystallized from isopropyl alcohol-isopropyl ether-water, giving 1.4 g(26%). Recrystallization from isopropyl alcohol-isopropyl ether gave 1.2g of a white solid, mp 212°-213° C.

Analysis: Calculated for C₂₂ H₂₄ N₆ O₅ : C, 58.40; H, 5.35; N, 18.57.Found: C, 58.10; H, 5.34; N, 18.33.

EXAMPLE 58 2-(2-Pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidmethyl ester hydrochloride[1:1]

A solution of 2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(2.50 g, 0.010 mole), methanol (50 ml), concentrated sulfuric acid (5ml), and benzene (50 ml) was refluxed overnight with a Dean-Stark trap.The reaction was concentrated in vacuo, diluted with water (50 ml), andbasified with 10% potassium carbonate solution. The mixture wasextracted with methylene chloride (3×25 ml). The combined organicextracts were washed with water (25 ml), dried over sodium sulfate, andconcentrated in vacuo. The residue was dissolved in tetrahydrofuran andtreated with excess ethereal hydrogen chloride, giving 2.35 g (77%).Recrystallization twice from tetrahydrofuran-methanol gave 1.0 g of awhite solid, mp 188°-190° C.

Analysis: Calculated for C₁₄ H₁₃ N₄ O₂ Cl: C, 55.18; H, 4.30; N, 18.38.Found: C, 55.56; H, 4.30; N, 18.49.

EXAMPLE 59 N,N-Dimethyl-2-[3-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-[(3-trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine3-acetic acid (3.0 g, 0.0093 mole), 1,1'-carbonyldiimidazole(1.5 g, 0.0093 mole) and anhydrous tetrahydrofuran (75 ml) was stirredat room temperature for 41/2 hours with a stream of nitrogen bubblingthrough. A solution (25 ml) of dimethylamine in tetrahydrofuran (2 g/100ml) was added and the reaction mixture was stoppered and stirredovernight. The resulting solution was concentrated in vacuo and theresidue was triturated in water (30 ml) and filtered. The filter cakewas again triturated in water (30 ml) and filtered, giving 2.6 g (80%),mp 136°-137.5° C. Recrystallization from tetrahydrofuran-petroleum ethergave 2.0 g of a white solid, mp 138°-139° C.

Analysis: Calculated for C₁₇ H₁₅ N₄ OF₃ : C, 58.62; H, 4.34; N, 16.08;Found: C, 58.44; H, 4.26; N, 16.00.

EXAMPLE 60N,Methyl-2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of 2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(2.44 g, 0.0096 mole), 1,1'-carbonyldiimidazole (1.56 g, 0.0096 mole),and anhydrous tetrahydrofuran (100 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through it for 5 hours. A solution of1M monomethylamine in tetrahydrofuran (15 ml) was added and the reactionstoppered and stirred overnight. The tetrahydrofuran was evaporated invacuo and the residue triturated in water (30 ml) and filtered. Thefilter cake was again triturated in water (30 ml) and filtered, giving1.94 g (76%) of solid, mp 228°-230° C. Recrystallization fromtetrahydrofuran-methanol gave 1.49 g of a white solid, mp 228.5°-230° C.

Analysis: Calculated for C₁₄ H₁₃ N₅ O: C, 62.91; H, 4.90; N, 26.20.Found: C, 62.62; H, 4.84; N, 26.12.

EXAMPLE 61 2-(2-Pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid1,1-dimethylethyl ester

Under a nitrogen atmosphere, N,N-dimethylformamide-ditert-butyl acetal(8.12 g, 0.040 mole) was added dropwise over a 20-minute period to astirred, refluxing suspension of2-(2-pyridyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.54 g, 0.010mole) in anhydrous benzene (50 ml). The resulting solution was refluxedfor 1 hour and allowed to cool to room temperature. The reaction mixturewas washed with 10% potassium carbonate solution (2×25 ml), water (25ml), dried over sodium sulfate and concentrated in vacuo. The residue(3.5 g) was dissolved in tetrahydrofuran and treated with excessethereal hydrogen chloride. The crystalline solid was recrystallizedfrom tetrahydrofuran, giving 1.5 g (43%). Drying in vacuo at 65° C. for8 hours and then at 78° C. overnight gave 1.4 g of the compound as thefree base, mp 124°-125.5° C.

Analysis: Calculated for C₁₇ H₁₈ N₄ O₂ : C, 65.79; H, 5.84; N, 18.05.Found: C, 65.44; H, 5.84; N, 17.99.

EXAMPLE 622-(4-Chlorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid(6.0 g, 0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in150 ml of tetrahydrofuran was stirred at room temperature for 2 hourswith a stream of nitrogen bubbling through it. A solution ofdi-n-propylamine (1.94 g, 0.063 mole) in tetrahydrofuran was addeddropwise at room temperature to the stirred solution and the reactionmixture was allowed to stir at room temperature overnight. Thetetrahydrofuran was evaporated and the solid residue was triturated withwater. The solid was collected by filtration and dried under high vacuumovernight. The solid was recrystallized from isopropyl alcohol-water,collected by filtration, washed with water, and dried under high vacuumat room temperature over the weekend to give 3.79 g (59%) in 2 crops, mp156°-57° C.

Analysis: Calculated for C₂₀ H₂₃ N₄ OCl: C, 64.77; H, 6.25; N, 15.11.Found: C, 64.60; H, 6.26; N, 15.08.

EXAMPLE 632-(3-Chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride[1:1]

A suspension of 2-(3-chlorophenyl)-3H-imidazo[4,5-b] pyridine-3-aceticacid (2.89 g, 0.010 mole), 1,1'-carbonyldiimidazole (1.62 g, 0.010mole), and anhydrous tetrahydrofuran (125 ml) was stirred at roomtemperature with a stream of nitrogen bubbling through it for 41/2hours. A solution of 1M methylamine in tetrahydrofuran (15 ml, 0.015mole) was added and the resulting solution was stoppered and stirredovernight at room temperature. The reaction mixture was concentrated invacuo and the residue triturated twice in water (2×75 ml) and filtered.The filter cake (mp 186°-189° C.) was dissolved in isopropyl alcohol andtreated with excess ethereal hydrogen chloride, giving 1.6 g (47%) of awhite flocculent solid which melted from 195°-199° C. after a fewcrystals had melted between 185°-190° C. It was also observed thatprolonged heating decreases the melting point.

Analysis: Calculated for C₁₅ H₁₄ N₄ OCl₂ : C, 53.43; H, 4.18; N,16.61.Found: C, 53.48; H, 4.20; N, 16.60.

EXAMPLE 642-(4-Chlorophenyl)-N,N-diethyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate[1:0.5]

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.64 g, 0.020 mole) and 1,1'-carbonyldiimidazole (3.18 g, 0.02 mole) in150 ml of tetrahydrofuran was stirred at room temperature for 2 hourswith a stream of nitrogen bubbling through it. A solution ofdiethylamine (2.87 g, 0.04 mole) in tetrahydrofuran was added dropwiseat room temperature to the stirred solution and the mixture was allowedto stir overnight. The tetrahydrofuran was evaporated and the solidresidue was triturated with water. The solid was collected by filtrationand dried under high vacuum overnight. The solid was recrystallized fromisopropyl alcohol-water, collected by filtration, washed with water, anddried under high vacuum at room temperature over the weekend to give3.83 g (57%) mp 155°-56° C.

Analysis: Calculated for C₁₈ H₁₉ N₄ OCl.1/2H₂ O: C, 61.45; H, 5.73; N,15.92. Found: C, 61.34; H, 5.46; N, 15.96.

EXAMPLE 652-(4-Chlorophenyl)-N-(1-methylethyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid(5.0 g, 0.017 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.017 mole) in150 ml of tetrahydrofuran was stirred at room temperature for 2 hourswith a stream of nitrogen bubbling through it. A solution ofisopropylamine (2.06 g, 0.035 mole) in tetrahydrofuran was addeddropwise and the reaction mixture was allowed to stir at roomtemperature overnight. The tetrahydrofuran was evaporated and the solidresidue was triturated with water. The solid was collected and driedunder high vacuum overnight. The solid was crystallized from isopropylalcohol with cooling in the freezer, collected by filtration, washedwith water, and dried under high vacuum at 50° C. overnight to give 4.0g (70%), mp 248°-9° C.

Analysis: Calculated for C₁₇ H₁₇ N₄ OCl: C, 62.10; H, 5.21; N, 17.04.Found: C, 61.95; H, 5.23; N, 17.05.

EXAMPLE 662-(4-Chlorophenyl)-N-(1-ethyl-3-piperidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:1]

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid(5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole)in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrshaving a stream of nitrogen bubbling through it.3-Amino-N-ethylpiperidine (4.46 g, 0.0348 mole) was added dropwise andthe reaction mixture was allowed to stir at room temperature overnight.

The tetrahydrofuran was evaporated and the residue was partitionedbetween methylene chloride and water. The methylene chloride layer wasseparated and extracted with dilute sodium hydroxide then with water.The methylene chloride layer was separated, dried, and evaporated. Theresidue was dried under high vacuum to give 5.2 g of solid.

The solid was dissolved in acetone, acidified with ethanolic andethereal hydrogen chloride and seeded. The solid was collected byfiltration, washed with tetrahydrofuran, and dried under high vacuum atroom temperature overnight. The solid was converted to the free basewith dilute sodium hydroxide and extracted with methylene chloride (3×).The combined methylene chloride extracts were washed with water, dried,and evaporated. The solid was dissolved in acetone, acidified withethanolic and ethereal hydrogen chloride, and seeded. The crystallinesolid was collected by filtration, washed with tetrahydrofuran, anddried under high vacuum at room temperature overnight, then at 50° C.for 2 hrs to give 2.24 g (27%) of title product, mp 208°-210° C.

Analysis: Calculated for C₂₁ H₂₄ N₅ OCl.2HCl.H₂ O: C, 51.60; H, 5.77; N,14.33. Found: C, 51.85; H, 5.66; N, 14.32.

EXAMPLE 671-[2-(4-Chlorophenyl)-1H-imidazo[4,5-b]pyridin-1-yl]-2-propanonehydrochloride[1:1]

The 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (2.29 g, 0.01 mole),was added to a suspension of sodium hydride (0.44 g of 60% sodiumhydride/oil, 0.01 mole, washed once with hexanes) in 50 ml ofdimethylformamide. The mixture was heated to 70° C. for 1 hr before theaddition of chloroacetone (0.93 g, 0.01 mole) at room temperature. Thereaction mixture was stirred at room temperature overnight, then pouredinto 300 ml of water. The precipitate was collected by filtration,washed with water, and dried under high vacuum at 50° C. overnight. Thesolid was recrystallized from methanol-water and dried under high vacuumat 50° C. overnight. The solid was dissolved in methanol, treated withcharcoal, and filtered through Celite to give a pale yellow filtrate.The filtrate was concentrated and diluted with water to initiatecrystallization. The precipitate was collected by filtration, washedwith water, and dried under high vacuum overnight. The solid wasdissolved in isopropyl alcohol, acidified with ethereal hydrogenchloride, diluted with isopropyl ether, and seeded to initiatecrystallization. The crystalline solid was collected by filtration,washed with isopropyl ether, and dried under high vacuum overnight togive 1.6 g, (50%), m.p. 220°-22° C.

Analysis: Calculated for C₁₅ H₁₃ N₃ OCl₂ : C, 55.92; H, 4.07; N, 13.04.Found: C, 55.49; H, 4.13; N, 13.06.

EXAMPLE 68 N-[[2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]glycine ethyl ester

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 5.0 g(0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Theethyl glycinate (2.65 g, 0.019 mole) and triethylamine (1.92 g, 0.019mole) were added dropwise and the reaction was allowed to stir at roomtemperature overnight.

The tetrahydrofuran was evaporated and the residue was partitionedbetween methylene chloride and water. The methylene chloride layer wasseparated and extracted with dilute sodium hydroxide then with water.The methylene chloride layer was separated, dried, and evaporated. A 2-gsample was recrystallized from ethanol-water. The crystalline solid wascollected by filtration, washed with water, and dried under high vacuumovernight to give 1.02 g (˜43%) of title compound, m.p. 191°-192° C.

Analysis: Calculated for C₁₈ H₁₇ N₄ O₃ Cl: C, 57.99; H, 4.60; N, 15.03.Found: C, 58.04; H, 4.46; N, 15.00.

EXAMPLE 692-(4-Chlorophenyl)-N-propyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetic acid5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole)in 150 ml of tetrahydrofuran was stirred at room temperature for 2.5 hrswith a stream of nitrogen bubbling through it. The n-propylamine (2.06g, 0.0348 mole) was added dropwise and the reaction mixture was allowedto stir at room temperature under nitrogen atmosphere overnight. Thetetrahydrofuran was evaporated and the residue was triturated withwater. The solid was collected and dried under high vacuum at 50° C.overnight. The solid was dissolved in isopropyl alcohol, filtered,diluted with water, and placed in the freezer overnight. The crystallineprecipitate was collected by filtration, washed with water, and dried at50° C. under high vacuum overnight to give 3.6 g (63%), m.p. 220°-21° C.

Analysis: Calculated for C₁₇ H₁₇ N₄ OCl: C, 62.10; H, 5.21; N, 17.04.Found: C, 61.99; H, 5.22; N, 17.05.

EXAMPLE 70N-[[2-(3-Chlorophenyl)-3H-imidazo[4,5-]pyridin-3-yl]acetyl]glycine ethylester

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(9.50 g, 0.033 mole), 1,1'-carbonyldiimidazole (5.35 g, 0.033 mole) andanhydrous tetrahydrofuran (300 ml) was stirred at room temperature for 2hrs with a stream of nitrogen bubbling through it. To the resultingsuspension was added glycine ethyl ester (8.0 g, 0.078 mole) and thesolution stirred over the weekend. The reaction mixture was filtered andthe filtrate concentrated in vacuo. The residue was partitioned betweenethyl acetate (150 ml) and potassium bicarbonate solution (75 ml). Theorganic layer was washed with potassium bicarbonate solution (2×50 ml),water (50 ml), brine (25 ml), dried over sodium sulfate, andconcentrated in vacuo. The residue (10 g) was recrystallized fromtetrahydrofuran-isopropyl ether to give 6.93 g (56%) of an off-whitesolid, m.p. 144°-145° C.

Analysis: Calculated for C₁₈ H₁₇ N₄ O₃ Cl: C, 57.99; h, 4.60; N, 15.03.Found: C, 58.00; H, 4.62; N, 15.03.

EXAMPLE 712-(4-Chlorophenyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3-imidazo[4,5-b]pyridine-3-acetamidehydrochloride[1:2]

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid5.0 g (0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole)in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrswith a stream of nitrogen bubbling through it. The2-(aminomethyl)-1-ethylpyrrolidine (4.46 g, 0.0348 mole) was addeddropwise and the reaction mixture was allowed to stir at roomtemperature overnight.

The tetrahydrofuran was evaporated and the residue was partitionedbetween methylene chloride and water. The methylene chloride layer wasseparated and extracted with dilute sodium hydroxide, then with water.The methylene chloride layer was separated, dried, and evaporated. Theresidue was dried under high vacuum overnight. The solid was dissolvedin isopropyl alcohol, acidified with ethereal hydrogen chloride, andseeded. The crystalline material was collected, washed withtetrahydrofuran and dried under high vacuum overnight. The solid wasconverted to the free base with dilute sodium hydroxide and extractedwith methylene chloride (3×). The combined methylene chloride extractswere washed with water, dried, evaporated, and dried under high vacuumovernight. The solid was dissolved in isopropyl alcohol, acidified withethanolic and ethereal hydrogen chloride, and seeded. The crystallinematerial was collected, washed with diethyl ether, and dried under highvacuum at 50° C. for 2 hrs, then at room temperature overnight. Thesample was redried under high vacuum at 50° C. overnight, at 70° C.overnight, and at room temperature overnight to give 5.0 g (61%) oftitle compound, m.p. 199°-202° C.

Analysis: Calculated for C₂₁ H₂₄ N₅ OCl.2HCl: C, 53.57; H, 5.67; N,14.60. Found: C, 53.10; H, 5.61; N, 14.62.

EXAMPLE 72N-[[2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]glycinepotassium salt hydrate [1:1:2]

A mixture of N-[[2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]glycine ethyl ester (4.0 g, 0.0108 mole), potassiumhydroxide (0.62 g, 0.011 mole), and 100 ml of 95% ethyl alcohol washeated at reflux for 2 hrs. The hot solution was filtered and allowed tocool to initiate crystallization. The solid was diluted with 95% ethylalcohol, filtered, and washed with a little 95% ethyl alcohol. The solidwas dried under high vacuum at room temperature overnight to give 2.5 g(55%) of title compound, m.p. >300° C.

Analysis: Calculated for C₁₆ H₁₂ N₄ O₃ Cl.K.2H₂ O: C, 45.88; H, 3.85; N,13.38. Found: C, 45.58; H, 3.80; N, 13.33.

EXAMPLE 732-(4-Chlorophenyl)-N-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen atmosphere, oxalyl chloride, 1.73 g (0.0137 mole) wasadded dropwise to a stirred, chilled (10°-15° C.) suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013mole) in 50 ml of dimethylformamide dried over molecular sieves. Thereaction mixture was heated at 60° C. for 5 hrs.

The solution of the acyl chloride prepared above was added dropwiseunder nitrogen atmosphere to a stirred and chilled (10°-15° C.) solutionof aniline (1.31 g, 0.014 mole), triethylamine (1.42 g, 0.014 mole), and75 ml of dry dimethylformamide. The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was poured into 200 ml ofwater and the solid was collected by filtration, washed with water, anddried under high vacuum overnight. The solid was recrystallized fromisopropyl alcohol with refrigeration overnight. The crystalline materialwas collected by filtration, washed with water, and dried under highvacuum at 70° C. overnight to give 3.11 g of title compound (66%), m.p.240°-42° C.

Analysis: Calculated for C₂₀ H₁₅ N₄ OCl: C, 66.21; H, 4.17; N, 15.44.Found: C, 66.17; H, 4.25; N, 15.34.

EXAMPLE 742-(4-Chlorophenyl)-N-(1-ethyl-3-pyrrolidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:1]

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid,(5.0 g, 0.0174 mole) and 1,1,'-carbonyldiimidazole (2.82 g, 0.0174 mole)in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs.3-Amino-N-ethylpyrrolidine (2.18 g, 0.019 mole) was added dropwise andthe reaction mixture was allowed to stir at room temperature overnight.

The tetrahydrofuran was evaporated and the residue was partitionedbetween methylene chloride and water. The methylene chloride layer wasseparated and extracted with dilute sodium hydroxide, then with water.The methylene chloride layer was separated, dried, and evaporated. Theresidue was triturated with water and dried under high vacuum overnight.The solid was dissolved in acetone, acidified with ethanolic hydrogenchloride, diluted with ethereal hydrogen chloride to the cloud point andseeded. The crystalline material was collected by filtration, washedwith acetone, and dried under high vacuum at 70° C. overnight to give5.83 g (71%) of crystals, m.p. 170°-72°C.

Analysis: Calculated for C₂₀ H₂₂ N₅ OCl.2 HCl.1 H₂ O: C, 50.59; H, 5.52;N, 14.75. Found: C, 50.69; H, 5.57; N, 14.73.

EXAMPLE 754-[[[2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]amino]butanoicacid ethyl ester

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole)in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs.Then, under nitrogen atmosphere, 4-aminobutyric acid ethyl esterhydrochloride (3.19 g, 0.019 mole) and triethylamine (1.92 g, 0.019mole) were added simultaneously and the reaction mixture was allowed tostir at room temperature overnight. The tetrahydrofuran was evaporatedto dryness and the residue was partitioned between methylene chlorideand water. The combined methylene chloride layers were extracted withdilute sodium hydroxide, then with water. The methylene chloride layerwas separated, dried, and evaporated to dryness (5.3 g) (76% crudeyield). A 2-g sample was recrystallized from absolute ethanol, and driedunder high vacuum overnight to give 1.47 g, mp. 169°-71° C.

Analysis: Calculated for C₂₀ H₂₁ N₄ O₃ Cl: C, 59.93; H, 5.28; N, 13.98.Found: C, 59.76; H, 5.28; N, 13.94.

EXAMPLE 762-(3-Chlorophenyl)-N-(3-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:2]

Under a nitrogen atmosphere, oxalyl chloride (1.41 ml, 0.015 mole) wasadded dropwise (slowly) to a stirred and chilled (25°-30° C.) solutionof 2-(3-chlorophenyl)-3H-imidazo[4,5-b] pyridine-3-acetic acid (4.00 g,0.0138 mole) in anhydrous dimethylformamide (75 ml). The reactionmixture was heated at 55°-60° C. for 31/2 hrs, cooled to roomtemperature, and added dropwise to a stirred and chilled (15°-20° C.)solution of 3-aminopyridine (1.50 g, 0.016 mole) and triethylamine (1.62g, 0.016 mole) in anhydrous dimethylformamide (25 ml). The reactionmixture was stirred at room temperature overnight, filtered, and pouredinto ice water (500 ml). The mixture was extracted with ethyl acetate(3×75 ml). The combined organic portions were washed with 5% potassiumhydroxide solution (2×50 ml), water (50 ml), brine (25 ml), dried oversodium sulfate and concentrated in vacuo. The residue was dissolved intetrahydrofuran and treated with excess ethereal hydrogen chloride andisopropyl ether giving 2.5 g (41%). Recrystallization from isopropylalcohol-ethanol-isopropyl ether gave 0.82 g. This was combined with asecond crop of 0.43 g to give an off-white solid which underwent a phasechange from 157°-163° C. and then decomposed at 186°-192° C.

Analysis: Calculated for C₁₉ H₁₆ N₅ OCl₃ : C, 52.26; H, 3.69; N, 16.04.Found: C, 52.16; H, 3.84; N, 15.92.

EXAMPLE 77 2-(3-Chlorophenyl)-N-[3-(dimethylamino)propyl]-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride [1:2]

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.76 g, 0.020 mole), 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole), andanhydrous tetrahydrofuran (250 ml) was stirred at room temperature witha stream of nitrogen bubbling through it for 2 hrs. The nitrogen flowwas stopped and a solution of 3-dimethylaminopropylamine (2.04 g, 0.020mole) in dry tetrahydrofuran (50 ml) was added. The solution wasstoppered and stirred at room temperature over the weekend. The reactionmixture was concentrated in vacuo and partitioned between ethyl acetate(100 ml) and 5% potassium hydroxide (50 ml). The layers were separatedand the aqueous portion washed with ethyl acetate (50 ml). The combinedorganic portions were washed with 5% potassium hydroxide solution (25ml), water (25 ml), brine (25 ml), dried over sodium sulfate, andconcentrated in vacuo. The solid residue was converted to thedihydrochloride salt and crystallized fromacetone-ethanol-tetrahydrofuran to give 3.23 g (36%) of a white granularsolid, mp. 203°-209° C. with decomposition.

Analysis: Calculated for C₁₉ H₂₄ N₅ OCl₃ : C, 51.31; H, 5.44; N, 15.74.Found: C, 51.26; H, 5.49; N, 15.70.

EXAMPLE 782-(3-Chlorophenyl)-N-(1-ethyl-2-pyrrolidinylmethyl)-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride [1:2]

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.76 g, 0.020 mole), 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole), andanhydrous tetrahydrofuran (250 ml) was stirred at room temperature witha stream of nitrogen bubbling through for 2 hrs. The nitrogen flow wasstopped and a solution of 2-(aminomethyl)-1-ethyl pyrrolidine (2.56 g,0.02 mole) in dry tetrahydrofuran (50 ml) was added. The solution wasstoppered and stirred at room temperature over the weekend. The reactionwas concentrated in vacuo and partitioned between ethyl acetate (100 ml)and 5% potassium hydroxide soluton (50 ml). The layers were separatedand the aqueous portion washed with ethyl acetate (50 ml), water (25ml), brine (25 ml), dried over sodium sulfate, and concentrated invacuo. The solid residue was converted to the dihydrochloride salt andcrystallized from isopropyl alcohol-diethyl ether. Recrystallizationfrom isopropyl alcohol-isopropyl ether gave 1.38 g (15%) of an off-whitesolid, mp 186°-190° C. with decomposition.

Analysis: Calculated for C₂₁ H₂₆ N₅ OCl₃ : C, 53.57; H, 5.57; N, 14.87.Found: C, 53.56; H, 5.60; N, 14.86.

EXAMPLE 792-(3-Chlorophenyl)-N-(1-ethyl-3-piperidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:1]

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.76 g, 0.020 mole), 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole), andanhydrous tetrahydrofuran (250 ml) was stirred at room temperature witha stream of nitrogen bubbling through it for 21/2 hrs. The nitrogen flowwas stopped and a solution of 3-amino-N-ethylpiperidine (2.56 g, 0.020mole) in dry tetrahydrofuran (50 ml) was added. The solution wasstoppered and stirred at room temperature for 2 hrs. The reaction wasconcentrated in vacuo and partitioned between ethyl acetate (150 ml) andpotassium bicarbonate solution (50 ml). The layers were separated andthe organic portion was washed with potassium bicarbonate solution (2×50ml), water (50 ml), brine (25 ml), dried over sodium sulfate, andconcentrated in vacuo. The solid residue (3.4 g) was converted to thehydrochloride salt and twice recrystallized fromacetone-tetrahydrofuran-ethanol to give 2.7 g (31%) of a white solid,mp. 275°-276° C. with decomposition.

Analysis: Calculated for C₂₁ H₂₅ N₅ OCl₂ : C, 58.07; H, 5.80; N, 16.12Found: C, 57.92; H, 5.90; N, 15.88

EXAMPLE 80 2-(3-Chlorophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride[1:1]

Under a nitrogen atmosphere, oxalyl chloride (2.8 ml, 0.032 mole) wasadded dropwise (slowly) to a stirred and chilled solution of2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.028mole) in anhydrous dimethylformamide (100 ml). The reaction was heatedat 55°-60° C. for 3 hrs, cooled to room temperature, and added dropwiseto a stirred and chilled (5°-10° C.) suspension ofN,N-dimethyl-p-phenylenediamine dihydrochloride (6.7 g, 0.032 mole) andtriethylamine (12.9 g, 0.128 mole) in anhydrous dimethylformamide (200ml). The reaction was stirred at room temperature over the weekend,filtered, and poured into ice water (600 ml). The mixture was filteredand the filter cake recrystallized from ethanol giving 6.6 g (58%). Thesolid was converted to the hydrochloride salt in isopropyl alcohol andconcentrated hydrochloric acid to give 6.6 g of a white granular solid,mp. 229°-231° C. with decomposition.

Analysis: Calculated for C₂₂ H₂₁ N₅ OCl₂ : C, 59.74; H, 4.78; N, 15.83.Found: C, 59.94; H, 4.86; N, 15.78.

EXAMPLE 812-(4-Chlorophenyl)-N-[2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:1:0.5]

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174mole) and 2.82 g (0.0174 mole) of 1,1'-carbonyldiimidazole in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hrs.N-(2-aminoethyl)piperidine (4.46 g, 0.0348 mole) was added dropwise andthe reaction mixture was allowed to stir at room temperature overnight.

The tetrahydrofuran was evaporated and the residue was partitionedbetween methylene chloride and water. The methylene chloride layer wasseparated and extracted with dilute sodium hydroxide, then with water.The methylene chloride layer was separated, dried, and evaporated. Theresidue was dried under high vacuum for 4-5 hrs (7.0 g).

A 4.8-g sample of the solid residue was dissolved in acetone, acidifedwith ethanolic and ethereal hydrogen chloride to produce a solid, whichwas collected by filtration, washed with tetrahydrofuran, and driedunder high vacuum overnight. The solid was converted to the free basewith dilute sodium hydroxide and extracted with methylene chloride (3×).The combined methylene chloride extracts were washed with water (1×),dried, and evaporated to a solid, which was triturated with water. Thesolid was collected by filtration and placed under high vacuumovernight. The solid was dissolved in isopropyl alcohol, acidified withethanolic hydrogen chloride, diluted with isopropyl ether, and seeded toinitiate crystallization. The crystalline precipitate was collected byfiltration, washed with cold isopropyl alcohol, and dried under highvacuum at 50° C. over the weekend to give 2.7 g (˜56%) of titlecompound, mp. 188°-90° C.

Analysis: Calculated for C₂₁ H₂₄ N₅ OCl.HCl.1/2 H₂ O: C, 56.89; H, 5.91;N, 15.80. Found: C, 56.54; H, 5.81; N, 15.79.

EXAMPLE 82 2-(4-Chlorophenyl)-N-[3-(dimethylamino)propyl]-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:1]

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hrs. Under anitrogen atmosphere, N,N-dimethylaminopropylamine (1.94 g, 0.019 mole)was added dropwise and the reaction was allowed to stir at roomtemperature overnight. The tetrahydrofuran was evaporated to dryness andthe residue was treated with ice water. The solid was collected byfiltration and dried under high vacuum. The solid was dissolved inisopropyl alcohol, acidified with ethereal hydrogen chloride, andseeded. The crystalline material was collected by filtration, washedwith cold isopropyl alcohol, and dried under high vacuum at 50° C. overthe weekend to give 2.78 g (34.5%), mp. 188°-90° C.

Analysis: Calculated for C₁₉ H₂₂ N₅ OCl.2HCl.H₂ O: C, 49.31; H, 5.66; N,15.13. Found: C, 49.34; H, 5.69; N, 15.20.

EXAMPLE 83N-[2-(Acetylamino)ethyl]-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor two hours with nitrogen bubbling through it. SolidN-acetylethylenediamine (4.44 g, 0.0435 mole) was added as well as 100ml of tetrahydrofuran. A solid formed. After stirring overnight undernitrogen, the reaction mixture was evaporated to a white solid which wastriturated in water (200 ml) overnight. The solid was collected byfiltration, rinsed with water, dissolved in hot isopropyl alcohol andfiltered hot. Water was added and the entire mixture was evaporated to asolid which was rinsed several times with light petroleum ether. Thesolid was dissolved in hot isopropyl alcohol and water was added to thecloud point. Upon cooling, solid precipitated, which was collected byfiltration, and recrystallized again from isopropyl alcohol. Uponaddition of water, the solid dissolved. All of the solvents were againevaporated under reduced pressure, and the resulting solid was againrecrystallized from isopropyl alcohol to give 1.20 g (18%) of titlecompound, mp 247°-249° C.

Analysis: Calculated for C₁₈ H₁₉ N₅ O₂.5 Cl: C, 56.77; H, 5.03; N,18.39. Found: C, 57.15; H, 5.00; N, 18.14.

EXAMPLE 844-[[[2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]amino]butanoicacid ethyl ester

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(8.0 g, 0.028 mole), 1,1'-carbonyldiimidazole (4.5 g, 0.028 mole), andanhydrous tetrahydrofuran (100 ml) was stirred at room temperature witha stream of nitrogen bubbling through it for 3 hours. The nitrogen flowwas stopped and triethylamine (6.3 g, 0.062 mole) and ethyl4-aminobutyrate hydrochloride (5.2 g, 0.031 mole) was added all at once.The reaction mixture was stirred under nitrogen over the weekend. Thetetrahydrofuran was evaporated and the solid residue triturated in water(100 ml) and filtered off to give 4.7 g (42%) of cake. A 2.3-g portionof the filter cake was recrystallized from isopropyl ether-ethanol togive 1.9 g of white solid, mp 127°-129° C.

Analysis: Calculated for C₂₀ H₂₁ N₄ O₃ Cl: C, 59.93; H, 5.28; N, 13.98.Found: C, 59.89; H, 5.28; N, 14.08.

EXAMPLE 852-(3-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(6.7 g, 0.00233 mole), 1,1'-carbonyldiimidazole (4.0 g, 0.0245 mole),and anhydrous tetrahydrofuran (150 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through for 21/2 hours. The nitrogenflow was stopped and a solution of N,N-dimethylethylenediamine (2.3 g,0.0257 mole) in dry tetrahydrofuran (50 ml) was stirred at roomtemperature under nitrogen for 2 hours. The reaction was concentrated invacuo and partitioned between methylene chloride (75 ml) and water (75ml). The layers were separated and the aqueous portion washed withmethylene chloride (25 ml). The combined organic portions were washedwith potassium bicarbonate solution (2×50 ml), water (25 ml), dried oversodium sulfate, and concentrated in vacuo. The solid residue, 5.7 g(68%) was recrystallized from isopropyl alcohol-isopropyl ether to give4.0 g of off-white granular solid, mp 124°-125° C.

Analysis: Calculated for C₁₈ H₂₀ N₅ OCl: C, 60.42; H, 5.63; N, 19.57.Found: C, 60.52; H, 5.69; N, 19.69.

EXAMPLE 862-(3-Chlorophenyl)-3-[2-oxo-2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.017 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.018 mole), andanhydrous tetrahydrofuran (100 ml) was stirred at room temperature witha stream of nitrogen bubbling through it for 3 hours. The nitrogen flowwas stopped and a solution of piperidine (1.6 g, 0.019 mole) in drytetrahydrofuran (50 ml) was added. The solution was stirred at roomtemperature under nitrogen for 2 hours. The reaction was concentrated invacuo and the residue triturated in water (100 ml) and the mix wasfiltered. The filter cake was recrystallized from isopropylalcohol-isopropyl ether to give 3.4 g (56%) of off-white flakes, mp149°-150° C.

Analysis: Calculated for C₁₉ H₁₉ N₄ OCl: C, 64.31; H, 5.40; N, 15.79.Found: C, 64.18; H, 5.32; N, 15.73.

EXAMPLE 872-(4-Bromophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.5 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.7 g, 0.0166mole), and anhydrous tetrahydrofuran (100 ml) was stirred at roomtemperature with a stream of nitrogen bubbling through it for 21/2hours. The nitrogen flow was stopped and a solution of dimethylamine(0.5M in tetrahydrofuran) (66 ml) was added. The solution was stirred atroom temperature, stoppered, for 16 hours. The reaction mixture wasconcentrated in vacuo and the residue triturated in water (100 ml) andfiltered. The filter cake was recrystallized from ethanol to give 3.78 g(63%) of white needles, mp 224°-225° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OBr: C, 53.50; H, 4.21; N, 15.60.Found: C, 53.55; H, 4.19; N, 15.68.

EXAMPLE 882-(4-Chlorophenyl)-N-(2-propenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 130 mltetrahydrofuran was stirred at room temperature for 3 hours. Under anitrogen atmosphere, N-allylamine (1.60 g, 0.028 mole) was added and thereaction mixture was allowed to stir at room temperature overnight. Thetetrahydrofuran was evaporated to a solid, which was placed under highvacuum over the weekend. The solid residue was dissolved in isopropylalcohol, filtered, and diluted with water to initiate crystallization,then refrigerated overnight. The solid was collected by filtration,washed with water, and dried under high vacuum at 50° C. overnight togive 3.0 g (66%) of title compound, mp 208°-9° C.

Analysis: Calculated for C₁₇ H₁₅ N₄ OCl: C, 62.48; H, 4.63; N, 17.14.Found: C, 62.53; H, 4.64; N, 17.18.

EXAMPLE 89 2-(4-Bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

N-[3-[(4-bromobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (4.6 g,0.012 mole) was heated in glass in a 190° C. oil bath for 1/2 hour. Themelt was cooled and methylene chloride (150 ml) added. The solution wastwice treated with 25 g of Florisil® and filtered. The filtrate wasconcentrated in vacuo and the residue recrystallized from isopropylether-ethanol to give 2.1 g (49%) of a white flocculent solid, mp138°-139° C.

Analysis: Calculated for C₁₆ H₁₄ N₃ O₂ Br: C, 53.35; H, 3.92; N, 11.66.Found: C, 55.16; H, 3.92; N, 11.70.

EXAMPLE 902-(4-Bromophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.5 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole)in anhydrous tetrahydrofuran (100 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through it for 21/2 hours. Thenitrogen flow was stopped and a solution of monomethylamine (1M intetrahydrofuran) (33 ml) was added. The solution was stoppered andstirred at room temperature for 16 hours. The reaction mixture wasconcentrated in vacuo and the residue triturated in water (100 ml) andfiltered. The filter cake (5.5 g, 96%) was recrystallized fromtetrahydrofuran-ethanol to give 3.0 g of a white flocculent solid, mp258°-259° C. after forming a polymorph from 250°-255° C.

Analysis: Calculated for C₁₅ H₁₃ N₄ OBr: C, 52.19; H, 3.80; N, 16.23.Found: C, 52.22; H, 3.78; N, 16.28.

EXAMPLE 912-(4-Bromophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:1]

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.5 g, 0.0166 mole) 1,1'-carbonyldiimidazole (2.7 g, 0.0166 mole)and anhydrous tetrahydrofuran (100 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through for 21/2 hours. The nitrogenflow was stopped and a solution of methylamine (1M in tetrahydrofuran)(33 ml, 0.0332 mole) was added. The solution was stirred at roomtemperature under nitrogen for 2 hours. The reaction mixture wasconcentrated in vacuo and the residue triturated in water (100 ml) andfiltered. The filter cake (5.5 g) was recrystallized fromtetrahydrofuran-ethanol to give 3.0 g (52%) of the free base of thetitle compound. The free base was converted to the hydrochloride salt inisopropyl alcoholisopropyl ether and the salt was recrystallized fromisopropyl alcohol-isopropyl ether to give white solid, mp 230°-232° C.

Analysis: Calculated for C₁₅ H₁₄ N₄ OBrCl: C, 47.20; H, 3.70; N, 14.68.Found: C, 47.27; H, 3.76; N, 14.52.

EXAMPLE 924-[[[2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]amino]butanoicacid potassium salt hydrate [1:1:1]

A mixture of4-[[[2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]amino]butanoicacid ethyl ester (3.3 g, 0.008 mole), potassium hydroxide (0.5 g, 0.009mole), and 80 ml of 95% ethyl alcohol was heated at reflux for13/4hours. The hot reaction mixture was filtered, washed with absoluteethanol, and the filtrate was evaporated to a solid residue. The solidwas triturated with acetone and filtered. The solid was dissolved in hottert-butanol and allowed to cool with seeding. The crystallineprecipitate was collected by filtration, washed with tert-butyl alcoholand dried under high vacuum at 50° C. overnight to give 1.2 g (35%) oftitle compound, mp 263°-264° C.

Analysis: Calculated for C₁₈ H₁₆ N₄ O₃ ClK·H₂ O: C, 50.14; H, 4.23; N,13.06. Found: C, 49.99; H, 4.05; N, 13.02.

EXAMPLE 932-(4-Chlorophenyl)-3-[2-oxo-2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole), in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours. Then, undernitrogen atmosphere, piperidine (1.31 g, 0.015 mole) was added and thereaction mixture was allowed to stir at room temperature overnight. Thetetrahydrofuran was evaporated to give a solid which was triturated withwater and dried under high vacuum over the weekend at 50° C. The solidwas recrystallized from isopropyl alcohol and refrigerated overnight.The crystalline material was collected by filtration, washed with coldisopropyl alcohol, and dried under high vacuum at 50° C. overnight togive 2.95 g (59%) of title compound, mp 176°-178° C.

Analysis: Calculated for C₁₉ H₁₉ N₄ OCl: C, 64.31; H, 5.40; N, 15.79.Found: C, 64.14; H, 5.39; N, 15.95.

EXAMPLE 942-(4-Chlorophenyl)-N-(phenylmethyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours. Then, undernitrogen atmosphere, benzylamine (1.58 g, 0.0147 mole) was added and thereaction was allowed to stir at room temperature overnight. Thetetrahydrofuran was evaporated, to give a solid. The solid wasrecrystallized from isopropyl alcohol, collected by filtration, washedwith cold isopropyl alcohol and water, and dried under high vacuum at50° C. overnight to give 3.43 g (65%) of title compound, mp 200°-200.5°C.

Analysis: Calculated for C₂₁ H₁₇ N₄ OCl: C, 66.93; H, 4.55; N, 14.88.Found: C, 66.98; H, 4.57; H, 15.06.

EXAMPLE 952-(4-Chlorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours. Then, undernitrogen atmosphere, cyclopropylamine (2.40 g, 0.042 mole) was added andthe reaction mixture was allowed to stir at room temperature overnight.The tetrahydrofuran was evaporated and the residue was recrystallizedfrom isopropyl alcohol with refrigeration. The solid was collected byfiltration, washed with cold isopropyl alcohol and water, and driedunder high vacuum at 50° C. over the weekend to give 2.4 g (53%) oftitle compound, mp 231°-232° C.

Analysis: Calculated for C₁₇ H₁₅ N₄ OCl: C, 62.48; H, 4.63; N, 17.14.Found: C, 62.61; H, 4.68; N, 17.10.

EXAMPLE 962-(4-Chlorophenyl)-3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours. Then, undernitrogen atmosphere, pyrrolidine (1.99 g, 0.028 mole) was added and thereaction mixture was allowed to stir at room temperature over theweekend. The precipitate which had formed was filtered and the filtratewas evaporated to dryness. The solid residue was triturated with waterand dried under high vacuum at 50° C. overnight. The solid wasrecrystallized from isopropyl alcohol with refrigeration. Theprecipitate was collected by filtration, washed with cold isopropylalcohol and water, and dried under high vacuum at room temperatureovernight to give 2.84 g (60%) of title compound, mp 224°-225° C.

Analysis: Calculated for C₁₈ H₁₇ N₄ OCl: C, 63.44; H, 5.03; N, 16.44.Found: C, 63.57; H, 5.04; N, 16.56.

EXAMPLE 972-(4-Bromophenyl)-N-(1-ethyl-3-pyrrolidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0151 mole), 1,1'-carbonyldiimidazole (2.45 g, 0.0151mole), and anhydrous tetrahydrofuran (100 ml) was stirred at roomtemperature with a stream of nitrogen bubbling through it for 3 hours.The nitrogen flow was stopped and a solution of1-ethyl-3-aminopyrrolidine (1.89 g, 0.0166 mole) in dry tetrahydrofuran(25 ml) was added. The solution was stirred at room temperature undernitrogen for 2 hours. The reaction mixture was concentrated in vacuo andthe residue triturated in water (100 ml) and filtered. The filter cakewas recrystallized from isopropyl alcohol-isopropyl ether to give 4.64 g(72%) of white needles, mp 202.5°-204° C.

Analysis: Calculated for C₂₀ H₂₂ N₅ OBr: C, 56.08; H, 5.18; N, 16.35.Found: C, 56.34; H, 5.20; N, 16.44.

EXAMPLE 982-(4-Bromophenyl)-N-(1-ethyl-3-pyrrolidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:1:1]

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0151 mole), 1,1'-carbonyldiimidazole (2.45 g, 0.0151mole), and anhydrous tetrahydrofuran (100 ml) was stirred at roomtemperature with a stream of nitrogen bubbling through it for 3 hours.The nitrogen flow was stopped and a solution of1-ethyl-3-aminopyrrolidine (1.89 g, 0.0166 mole) in dry tetrahydrofuran(25 ml) was added. The solution was stirred at room temperature undernitrogen for 2 hours. The reaction mixture was concentrated in vacuo andthe residue triturated in water (100 ml) and filtered. The filter cakewas recrystallized from isopropyl alcohol-isopropyl ether to give 4.64 g(72%) of the free base of the title compound. The organic filtrate wasconcentrated in vacuo, combined with 2.6 g of the free base obtained inExample 97, converted to the hydrochloride salt and crystallized fromisopropyl alcohol-isopropyl ether to give 2.6 g of an off-white solid,mp 177° -180° C., with decomposition after a phase change at 170°-173°C.

Analysis: Calculated for C₂₀ H₂₅ N₅ O₂ BrCl: C, 49.76; H, 5.22; N,14.50. Found: C, 49.36; H, 5.06; N, 14.25.

EXAMPLE 992-(4-Bromophenyl)-N-[2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (2.9 g, 0.018 mole)and anhydrous tetrahydrofuran (100 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through for 3 hours. The nitrogenflow was stopped and a solution of 1-(2-aminoethyl)piperidine (2.3 g,0.018 mole) in dry tetrahydrofuran (25 ml) was added. The solution wasstirred at room temperature under nitrogen for 2 hours. The reactionmixture was concentrated in vacuo and the residue triturated inpotassium bicarbonate solution (100 ml) and filtered. The filter cakewas washed with water and recrystallized from isopropylalcohol-isopropyl ether to give 5.8 g (73%) of off-white needles, mp178°-179° C.

Analysis: Calculated for C₂₁ H₂₄ N₅ OBr: C, 57.02; H, 5.47; N, 15.83.Found: C, 57.34; N, 5.52; N, 15.98.

EXAMPLE 1002-(4-Bromophenyl)-N-[2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:1]

2-(4-Bromophenyl)-N-[2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide(3.5 g, 0.0079 mole) was converted to the hydrochloride salt inisopropyl alcohol-isopropyl ether, using concentrated hydrochloric acidto acidify. Recrystallization from isopropyl alcohol-isopropyl ethergave 3.5 g (83%) of a white solid, mp 150°-153° C.

Analysis: Calculated for C₂₁ H₂₈ N₅ O₂ BrCl₂ : C, 47.30; H, 5.29; N,13.13. Found: C, 47.63; H, 5.35; N, 13.21.

EXAMPLE 1012-(4-Bromophenyl)-N-(1-ethyl-3-piperidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (3.1 g, 0.019 mole),and anhydrous tetrahydrofuran (100 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through it for 3 hours. The nitrogenflow was stopped and a solution of 3-amino-N-ethylpiperidine (2.6 g,0.020 mole) in dry tetrahydrofuran (25 ml) was added. The solution wasstirred at room temperature under nitrogen for 2 hours. The reactionmixture was concentrated in vacuo and the residue triturated inpotassium bicarbonate solution (100 ml) and filtered. The filter cakewas washed with water and recrystallized from isopropyl alcohol to give4.9 g, (62%) of a white solid, mp 190°-192° C.

Analysis: Calculated for C₂₁ H₂₄ N₅ OBr: C, 57.02; H, 5.47; N, 15.83.Found: C, 57.38; H, 5.52; N, 15.98.

EXAMPLE 1022-(4-Bromophenyl)-N-(1-ethyl-3-piperidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:1]

A sample of2-(4-bromophenyl)-N-(1-ethyl-3-piperidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide(4.8 g, 0.011 mole) was converted to the hydrochloride salt usingconcentrated hydrochloric acid in isopropyl alcohol. Recrystallizationfrom ethanol-isopropyl ether gave 3.58 g (61%) of white solid, mp179°-183° C. after a phase change at 168°-172° C.

Analysis: Calculated for C₂₁ H₂₈ N₅ O₂ BrCl₂ : C, 47.30; H, 5.29; N,13.13. Found: C, 47.32; H, 5.41; N, 12.85.

EXAMPLE 103N-[[2-(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]glycinepotassium salt hydrate [1:1:2]

A solution ofN-[[2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]glycineethyl ester (4.90 g, 0.0132 mole), and potassium hydroxide pellets (0.9g, 0.0161 mole) in ethanol (100 ml) was refluxed for 2 hours. Thereaction mixture was filtered and the filtrate volume reduced to 50 ml,giving 4.6 g (83%). Recrystallization from ethanol gave a whiteflocculent solid which, after drying overnight at 98° C. in vacuo, wasshown by NMR spectroscopy to be the hemihydrate of the potassium salt.When exposed to atmospheric moisture for 2 hours, the dihydrate formed,mp 295°-301° C.

Analysis: Calculated for C₁₆ H₁₆ N₄ O₅ ClK; C, 45.88; H, 3.85; N, 13.38.Found: C, 45.92; H, 3.67; N, 13.47.

EXAMPLE 1042-(4-Chlorophenyl)-N-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.014 mole) wasadded slowly to a stirred and chilled (10°-15° C.) suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013mole) in 50 ml of dry dimethylformamide. The reaction mixture was heatedbetween 60°-90° C. for 5 hours. The solution of the acyl chloride wasadded dropwise under a nitrogen atmosphere to a stirred, chilled(10°-15° C.) solution of 2-aminopyridine (1.77 g, 0.019 mole), andtriethylamine (1.90 g, 0.019 mole) in 75 ml of dry dimethylformamide.The reaction mixture was stirred at room temperature overnight. Thereaction mixture was poured into water, diluted with water to the cloudpoint, and seeded. The crystalline solid was collected by filtration,washed with water, and dried under high vacuum at 70° C. for 2 hours,then at 60° C. overnight to give 1.0 g (20%) of crystals, mp 190°-191°C.

Analysis; Calculated for C₁₉ H₁₄ N₅ OCl: C, 62.73; H, 3.88; N, 19.25.Found: C, 62.54; H, 3.95; N, 18.94.

EXAMPLE 1052-(4-Chlorophenyl)-N-cyclopentyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours.Cyclopentylamine (2.38 g, 0.028 mole) was added and the reaction mixturewas allowed to stir at room temperature overnight. The tetrahydrofuranwas evaporated to dryness and the residue was treated with water. Thesolid was collected by filtration, washed with water, and dried underhigh vacuum overnight. The solid was recrystallized from isopropylalcohol-ethanol, collected by filtration, washed with cold isopropylalcohol, and dried under high vacuum over the weekend to give 3.67 g(74%) of crystals, mp 260°-261° C.

Analysis: Calculated for C₁₉ H₁₉ N₄ OCl: C, 64.31; H, 5.40; N, 15.79.Found: C, 64.16; H, 5.39; N, 15.84.

EXAMPLE 1062-(4-Chlorophenyl)-N-(cyclopropylmethyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 4 hours.Aminomethylcyclopropane hydrochloride (3.01 g, 0.028 mole) andtriethylamine (2.83 g, 0.028 mole) were added and the reaction mixturewas allowed to stir at room temperature overnight. The tetrahydrofuranwas evaporated to dryness and the residue was treated with water. Thesolid was collected by filtration, washed with water, and dried underhigh vacuum overnight. The solid was recrystallized from isopropylalcohol with cooling. The crystalline precipitate was collected byfiltration, washed with cold isopropyl alcohol and water, and driedunder high vacuum at 60° C. overnight to give 3.92 g (82%) of crystals,mp 228°-229° C.

Analysis: Calculated for C₁₈ H₁₇ N₄ OCl: C, 63.44; H, 5.03; N, 16.44.Found: C, 63.28; H, 5.00; N, 16.54.

EXAMPLE 1072-(4-Chlorophenyl)-N-cyclohexyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours.Cyclohexylamine (2.77 g, 0.028 mole) was added and the reaction mixturewas allowed to stir at room temperature overnight. The tetrahydrofuranwas evaporated to dryness and the residue was treated with water. Thesolid was collected by filtration, washed with water, and dried underhigh vacuum over the weekend. The solid was recrystallized fromisopropyl alcohol-95% ethanol, collected by filtration, washed withwater, and dried under high vacuum at 50° C. overnight to give 3.75 g(73%) of crystals, mp 240°-241° C.

Analysis: Calculated for C₂₀ H₂₁ N₄ OCl: C, 65.12; H, 5.74; N, 15.19.Found: C, 65.18; H, 5.72; N, 15.28.

EXAMPLE 1082-(3-Chlorophenyl)-N-(1-ethyl-3-pyrrolidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:0.5]

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) andanhydrous tetrahydrofuran (100 ml) was stirred at room temperature witha stream of nitrogen bubbling through it for 3 hours. The nitrogen flowwas stopped and a solution of 1-ethyl-3-aminopyrrolidine (2.18 g, 0.0192mole) in dry tetrahydrofuran (25 ml) was added. The solution was stirredat room temperature under nitrogen for 1 hour. The reaction mixture wasconcentrated in vacuo and the residue triturated in potassiumbicarbonate solution (75 ml) and filtered. The filter cake was washedwith water and recrystallized from isopropyl alcohol-isopropyl ether togive 2.25 g (28%) of beige solid, mp 154°-157° C.

Analysis: Calculated for C₂₀ H₂₂ N₅ OCl: C, 51.57; H, 5.41; N,15.03.2HCl. 0.5H₂ O Found: C, 51.49; H, 5.55; N, 14.90.

EXAMPLE 1092-(4-Bromophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0151 mole), 1,1'-carbonyldiimidazole (2.45 g, 0.0151mole), and anhydrous tetrahydrofuran (100 ml) was stirred at roomtemperature with a stream of nitrogen bubbling through it for 3 hours.The nitrogen flow was stopped and a solution ofN,N-dimethylethylenediamine (1.46 g, 0.0166 mole) in dry tetrahydrofuran(25 ml) was added. The solution was stirred at room temperature undernitrogen for 2 hours. The reaction mixture was concentrated in vacuo andthe residue triturated in water (100 ml) and filtered. The filter cakewas recrystallized from ethanolisopropyl ether-tetrahydrofuran to give4.45 g (73%) of white flakes, mp 195°-197° C.

Analysis: Calculated for C₁₈ H₂₀ N₅ OBr: C, 53.74; H, 5.01; N, 17.41.Found: C, 53.63; H, 5.04; N, 17.57.

EXAMPLE 1102-(4-Bromophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:0.5]

2-(4-Bromophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide(2.25 g, 0.0056 mole) was treated with concentrated hydrochloric acidand isopropyl alcohol to give 2.4 g precipitate. Recrystallization fromisopropyl alcohol gave 1.9 g (70%) of white solid, mp 160.5°-162° C.

Analysis: Calculated for C₁₈ H₂₃ N₅ O₁.5 BrCl₂ : C, 44.65; H, 4.79; N,14.46. Found: C, 44.68; H, 5.01; N, 14.52.

EXAMPLE 1112-(3-Chlorophenyl)-N-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (4.6 g, 0.037 mole) wasadded dropwise (slowly) to a stirred and chilled (10°-15° C.) solutionof 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g,0.035 mole) in anhydrous dimethylformamide (100 ml). The reactionmixture was heated at 55°-60° C. for 5 hours, cooled to roomtemperature, and added dropwise to a stirred and chilled (10°-15° C.)solution of aniline (3.5 g, 0.038 mole) and triethylamine (7.6 g, 0.076mole) in anhydrous dimethylformamide (75 ml). The reaction was stirredat room temperature overnight, poured into water (500 ml), allowed toprecipitate, and filtered. The filter cake was twice suspended inpotassium bicarbonate solution (250 ml) and filtered. The filter cakewas washed with water, air dried, and recrystallized from ethanol,giving 4.74 g (37%) of off-white needles, mp 211°-212° C.

Analysis: Calculated for C₂₀ H₁₅ N₄ OCl: C, 66.28; H, 4.17; N, 15.44,Found: C, 66.00; H, 4.23; N, 15.43,

EXAMPLE 112N-(2-Chlorophenyl)-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.014 mole) wasadded slowly to a stirred and chilled (10°-15° C.) suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013mole) in 50 ml of dimethylformamide. The reaction mixture was heated at60° C. for 5 hours. The solution of the acyl chloride prepared above wasadded dropwise under nitrogen atmosphere to a stirred and chilled(10°-15° C.) solution of o-chloroaniline (1.79 g, 0.014 mole),triethylamine (1.42 g, 0.014 mole), and 75 ml of dimethylformamide.After the addition, the reaction mixture was allowed to stir at roomtemperature overnight. The reaction mixture was poured into 200 ml ofwater. The crystalline solid was collected by filtration, washed withwater, and dried under high vacuum overnight to give 2.76 g (54%) ofcrystals, mp 232°-235.5° C.

Analysis: Calculated for C₂₀ H₁₄ N₄ OCl₂ : C, 60.47; H, 3.55; N, 14.10,Found: C, 60.37; H, 3.58; N, 14.09,

EXAMPLE 1132-(3-Chlorophenyl)-N-[2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.4 g, 0.0188 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.0188 mole) inanhydrous tetrahydrofuran (150 ml) was stirred at room temperature witha stream of nitrogen bubbling through it for 21/2 hours. The nitrogenflow was stopped and a solution of 1-(2-aminoethyl)piperidine (2.4 g,0.0188 mole) in dry tetrahydrofuran (50 ml) was added. The solution wasstirred at room temperature under nitrogen for 2 hours. The reactionmixture was concentrated in vacuo and the residue partitioned betweenmethylene chloride (75 ml) in water (75 ml). The layers were separatedand the aqueous portion washed with methylene chloride (25 ml). Theorganic layers were combined and washed with potassium bicarbonatesolution (2×50 ml), water (25 ml), dried over sodium sulfate, andconcentrated in vacuo. The residue (6.6 g) was recrystallized fromisopropyl alcohol-isopropyl ether to give 3.5 g (47%). Recrystallizationfrom isopropyl alcohol-isopropyl ether gave 2.5 g of cream coloredsolid, mp 114°-115° C.

Analysis: Calculated for C₂₁ H₂₄ N₅ OCl: C, 63.39; H, 6.08; N, 17.60.Found: C, 63.34; H, 6.16; N, 17.69.

EXAMPLE 1142-(4-Bromophenyl)-3-[2-oxo-2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

A suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (6.0 g, 0.018 mole), 1,1'-carbonyldiimidazole (3.1 g, 0.019 mole),and anhydrous tetrahydrofuran (100 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through for 3 hours. The nitrogenflow was stopped and a solution of piperidine (1.7 g, 0.020 mole) in drytetrahydrofuran (25 ml) was added. The solution was stirred at roomtemperature under nitrogen for 2 hours. The reaction mixture wasconcentrated in vacuo and the residue triturated in potassiumbicarbonate solution (100 ml) and filtered. The filter cake was washedwith water and recrystallized from isopropyl alcohol-isopropyl ether togive 5.9 g (82%) of white flakes, mp 175°-176° C.

Analysis: Calculated for C₁₉ H₁₉ N₄ OBr: C, 57.15; H, 4.80; N, 14.03.Found: C, 57.22; H, 4.83; N, 14.15.

EXAMPLE 1152-(4-Chlorophenyl)-N-methyl-N-(phenylmethyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours. Thebenzylmethylamine (1.95 g, 0.016 mole) was added and the reactionmixture was allowed to stir at room temperature for 3 hours. Thetetrahydrofuran was evaporated to dryness and the residue waspartitioned between methylene chloride and saturated sodium bicarbonate.The aqueous layer was separated and extracted with methylene chloride(2×). The methylene chloride extracts were combined and extracted withwater (1×). The methylene chloride layer was dried over magnesiumsulfate, evaporated to dryness, and placed under high vacuum at roomtemperature overnight. The oil was dissolved in hot isopropyl alcohol,diluted with water, and seeded to produce crystalline needles, thenrefrigerated. The solid was collected by filtration, washed with water,and dried at 50° C. overnight under high vacuum to give 4.08 g (75%) oftitle compound, mp 87°-89° C.

Analysis: Calculated for C₂₂ H₁₉ N₄ OCl: C, 67.60; H, 4.90; N, 14.33.Found: C, 67.47; H, 4.85; N, 14.39.

EXAMPLE 1162-(4-Bromophenyl)-N-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (3.2 g, 0.025 mole) wasadded dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.024mole) in anhydrous dimethylformamide (50 ml). The reaction mixture washeated at 55°-60° C. for 4 hrs, cooled to room temperature, and addeddropwise to a stirred and chilled (10°-15° C.) solution of2-chloroaniline (3.2 g, 0.25 mole) and triethylamine (2.5 g, 0.025 mole)in anhydrous dimethylformamide (100 ml). The reaction mixture wasstirred at room temperature overnight, filtered, and poured into water(350 ml). The mixture was allowed to precipitate and filtered. Thefilter cake was twice suspended in water (250 ml) and filtered. Thefilter cake was air dried and twice recrystallized from tetrahydrofuranto give 4.22 g (40%) of a white solid, mp. 230.5°-232° C.

Analysis: Calculated for C₂₀ H₁₄ N₄ OBrCl: C, 54.38; H, 3.19; N, 12.68.Found: C, 54.29; H, 3.18; N, 12.65.

EXAMPLE 1172-(4-Bromophenyl)-N-(3-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:2]

Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.0267 mole) wasadded dropwise (slowly) to a stirred and chilled (10° C.) solution of2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.4 g, 0.0254mole) in anhydrous dimethylformamide (50 ml). The reaction was heated at55°-60° C. for 4 hrs, cooled to room temperature, and added dropwise toa stirred and chilled (10° C.) solution of 3-aminopyridine (2.6 g,0.0279 mole) and triethylamine (5.4 g, 0.0534 mole) in anhydrousdimethylformamide (100 ml). The reaction was stirred at room temperatureovernight and then 100 ml of dimethylformamide was distilled off at 100mm Hg. The residue was cooled and triturated in potassium bicarbonatesolution (2×50 ml) and filtered. The filter cake was rinsed with water(2×50 ml) and recrystallized from isopropyl alcohol-isopropyl ether,giving 5.64 g (53%). Recrystallization from isopropyl alcohol-isopropylether gave 2.3 g of the free base hemihydrate of the title compound. Theorganic filtrates were combined and excess etherealhydrogen chlorideadded, giving 3.72 g. Recrystallization from isopropyl alcohol-isopropylether gave 3.0 g of an off-white solid, mp. 180°-186° C. after a phasechange at 176-178° C.

Analysis: Calculated for C₁₉ H₁₆ N₅ OBrCl₂ : C, 47.43; H, 3.35; N,14.55. Found: C, 47.26; H, 3.55; N, 14.50;

EXAMPLE 1182-(4-Bromophenyl)-N-(3-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.0267 mole) wasadded dropwise (slowly) to a stirred and chilled (10° C.) solution of2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.4 g, 0.0254mole) in anhydrous dimethylformamide (50 ml). The reaction was heated at55°-60° C. for 4 hrs, cooled to room temperature, and added dropwise toa stirred and chilled (10° C.) solution of 3-aminopyridine (2.6 g,0.0279 mole) and triethylamine (5.4 g, 0.0534 mole) in anhydrousdimethylformamide (100 ml). The reaction mixture was stirred at roomtemperature overnight and then 100 ml of dimethylformamide was distilledoff at 100 mm Hg. The residue was cooled and triturated in potassiumbicarbonate solution (2×50 ml) and filtered. The filter cake was rinsedwith water (2×50 ml) and recrystallized from isopropyl alcohol-isopropylether, giving 5.64 g (53%) of solids. Recrystallization from isopropylalcoholisopropyl ether gave 2.3 g of an off-white solid, mp. 215°-217°C.

Analysis: Calculated for C₁₉ H₁₅ N₅ O₁.5 Br: C, 54.69; H, 3.62; N,16.78. Found: C, 54.75; H, 3.72; N, 16.72.

EXAMPLE 119N,N-Dimethyl-2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:1:0.5]

A suspension of 2-(2-pyridyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(2.44 g, 0.0096 mole), 1,1'-carbonyldiimidazole (1.56 g, 0.0096 mole),and anhydrous tetrahydrofuran (75 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through for 41/2 hrs. The nitrogenflow was stopped and 25 ml of a solution of dimethylamine (2 g, 100 ml)in dry tetrahydrofuran (25 ml of 0.44M) was added. The solution wasstirred at room temperature under nitrogen for 12 hrs. The reactionmixture was concentrated in vacuo and the residue dissolved in ethylacetate (50 ml). The solution was washed with 5% potassium carbonatesolution (2×25 ml), water (25 ml), dried over sodium sulfate, andconcentrated in vacuo. The residue (1.1 g) was dissolved intetrahydrofuran-isopropyl ether and treated with excess etherealhydrogen chloride giving 1.0 g. The aqueous portions were combined,acidified with acetic acid, saturated with sodium chloride and filtered.The filter cake was dissolved in tetrahydrofuran and treated with excessethereal hydrogen chloride, giving 0.9 g. This was combined with the1.0-g sample and recrystallized from tetrahydrofuran-methanol.Trituration in tetrahydrofuran-isopropyl ether-ethereal hydrogenchloride gave 1.4 g (45%) of a white solid, mp. 171°-174° C. withdecomposition.

Analysis: Calculated for C₁₅ H₁₇ N₅ O₁.5 Cl: C, 55.18; H, 5.24; N,21.45. Found: C, 55.42; H, 5.16; N, 21.56.

EXAMPLE 1202-(4-Chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide-4-oxide

A mixture of2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide(0.3 g, 0.00096 mole), glacial acetic acid (2.5 ml), andm-chloroperbenzoic acid (0.66 g, 0.00384 mole) was heated at 60° C. fora total of 4 hrs. The reaction mixture was diluted with water and theorganic acid which precipitated was filtered. The aqueous filtrate wasneutralized for peroxides with 10% sodium sulfite. The aqueous solutionwas evaporated to dryness and the residue was dissolved in methylenechloride. The methylene chloride was extracted with a minimum ofsaturated sodium bicarbonate. The methylene chloride was dried andevaporated to a residue which crystallized upon standing. The solid wasrecrystallized from tetrahydrofuran-hexanes with refrigerationovernight. The solid was collected by filtration and dried under highvacuum overnight to give 0.28 g (88 %) of the title compound, mp200°-201.5° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ O₂ Cl: C, 58.10; H, 4.57; N, 16.94.Found: C, 58.04; H, 4.60; N, 16.86;

EXAMPLE 1212-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide-4-oxide

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide(1.84 g, 0.0064 mole), glacial acetic acid, and m-chloroperbenzoic acid(4.4 g, 0.0256 mole) was heated at 60° C. for a total of 4 hrs. Thereaction mixture was diluted with water and the organic acid whichprecipitated was filtered. The aqueous filtrate was neutralized forperoxides with 10% sodium sulfite. The aqueous solution was evaporatedto dryness and the residue was treated with methylene chloride/saturatedsodium bicarbonate. The insoluble precipitate was filtered, washed withmethylene chloride and water, and dried at 50° C. under high vacuumovernight to give 1.0 g (52%) of title compound, mp. 272°-75° C. withdecomposition.

Analysis: Calculated for C₁₄ H₁₁ N₄ O₂ Cl: C, 55.55; H, 3.66; N, 18.51.Found: C, 55.55; H, 3.64; N, 18.29.

EXAMPLE 1222-4-Chlorophenyl)-N,N-dibutyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g,0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Thedi-n-butylamine (2.59 g, 0.02 mole) was added and the reaction mixturewas heated at 60° C. for 3 hrs.

The tetrahydrofuran was evaporated to dryness and the residue waspartitioned between methylene chloride and saturated sodium bicarbonate.The aqueous layer was separated and extracted with methylene chloride.(2×). The methylene chloride extracts were combined and extracted withwater (1×). The methylene chloride layer was dried, evaporated, anddried under high vacuum overnight. The solid was recrystallized fromisopropyl alcohol-water. The solid was collected by filtration, washedwith water, and dried under high vacuum at 50° C. overnight to give 3.33g of title compound (48%), mp. 99°-101° C.

Analysis: Calculated for C₂₂ H₂₇ N₄ OCl: C, 66.24; H, 6.82; N, 14.04.Found: C, 66.09; H, 6.80; N, 14.07.

EXAMPLE 1232-(4-Bromophenyl)-N-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (3.4 g, 0.027 mole) wasadded dropwise (slowly) to a stirred and chilled (10° C.) suspension of2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.4 g, 0.025mole) in anhydrous dimethylformamide (50 ml). The reaction mixture washeated at 55°-60° C. for 4 hours, cooled to room temperature, and addeddropwise to a stirred and chilled (10° C.) solution of 2-aminopyridine(2.6 g, 0.028 mole) and triethylamine (5.4 g, 0.0053 mole) in anhydrousdimethylformamide (100 ml). The reaction was stirred at room temperatureovernight. Dimethylformamide (100 ml) was distilled off at 100 mm Hg.The residue was cooled, triturated in potassium bicarbonate solution(2×50 ml), and filtered. The filter cake was rinsed with water (2×50 ml)and recrystallized from ethanolisopropyl ether to give 4.8 g (47%) ofwhite solid, mp 191.5°-195° C.

Analysis: Calculated for C₁₉ H₁₄ N₅ OBr: C, 55.90; H, 3.46; N, 17.15.Found: C, 55.68; H, 3.76; N, 16.79.

EXAMPLE 1242-(4-Chlorophenyl)-N-[bis(2-propenyl)]-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.017mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.017 mole) in 150 ml oftetrahydrofuran was stirred at room temperature for 3 hours. Then, undernitrogen atmosphere, diallylamine (1.94 g, 0.02 mole) was added and thereaction mixture was allowed to stir at room temperature overnight. Thetetrahydrofuran was evaporated and the residue was partitioned betweenmethylene chloride and dilute sodium bicarbonate. The separated aqueouslayer was extracted with methylene chloride (2×). The combined methylenechloride extracts were extracted with water, dried over magnesiumsulfate, and evaporated to dryness. The residue was dried under highvacuum over the weekend. The solid was recrystallized from isopropylalcohol-water with refrigeration overnight. The solid was collected byfiltration, washed with water, and dried under high vacuum at 50° C.overnight to give 4.17 g (65%) of title compound, mp, 143°-145° C.

Analysis: Calculated for C₂₀ H₁₉ N₄ OCl: C, 65.48; H, 5.22; N, 15.27.Found: C, 65.08; H, 5.20; N, 15.25.

EXAMPLE 1252-(4-Bromophenyl)-N-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (2.6 g, 0.020 mole) wasadded dropwise (slowly) to a stirred and chilled (5°-10° C.) suspensionof 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3acetic acid (6.4 g,0.019 mole) in anhydrous dimethylformamide (50 ml). The reaction mixturewas heated at 55°-60° C. for 5 hours, cooled to room temperature, andadded dropwise to a stirred and chilled (10°-15° C.) solution of aniline(1.9 g, 0.020 mole) and triethylamine (2.1 g, 0.020 mole) in anhydrousdimethylformamide (100 ml). The reaction mixture was stirred at roomtemperature overnight, filtered, and poured into ice water (500 ml). Themixture was allowed to precipitate and was filtered. The filter cake wastriturated in potassium bicarbonate solution (100 ml), filtered, and thecake washed with water (100 ml). Recrystallization fromtetrahydrofuran-isopropyl ether and then isopropylalcohol-ethanoltetrahydrofuran gave 3.8 g (49%) of an off-white solid,mp 242°-243.5° C.

Analysis: Calculated for C₂₀ H₁₅ N₄ OBr: C, 58.98; H, 3.71; N, 13.76.Found: C, 58.90; H, 3.69; N, 13.71;

EXAMPLE 1262-(3-Bromophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (6.0 g, 0.018 mole) 1,1'-carbonyldiimidazole (2.9 g, 0.018 mole),and anhydrous tetrahydrofuran (200 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through for 4 hours. The nitrogenflow was stopped and a solution of methylamine in tetrahydrofuran (36 mlof 1M) was added. The solution was stirred at room temperature undernitrogen for 1/2 hour. The reaction mixture was filtered andconcentrated in vacuo and the residue triturated in water (100 ml) andfiltered. The filter cake was recrystallized fromtetrahydrofuran-isopropyl ether, giving 4.6 g (74%). Recrystallizationfrom isopropyl alcohol-isopropyl ether gave 4.4 g of off-white needles,mp 199°-201° C.

Analysis: Calculated for C₁₅ H₁₃ N₄ OBr: C, 52.19; H, 3.80; N, 16.23.Found: C, 52.13; H, 3.75; N, 16.15.

EXAMPLE 1272-(3-Bromophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (6.0 g, 0.018 mole), and 1,1'carbonyldiimidazole (2.9 g, 0.018mole), in anhydrous tetrahydrofuran (175 ml) was stirred at roomtemperature with a stream of nitrogen bubbling through it for 4 hours.The nitrogen flow was stopped and a solution of dimethylamine intetrahydrofuran (72 ml of 0.5M) was added. The solution was stirred atroom temperature under nitrogen for 1/2 hour. The reaction mixture wasfiltered, concentrated in vacuo and the residue triturated in water (100ml) and filtered. The filter cake was recrystallized fromtetrahydrofuran-isopropyl ether, giving 4.5 g (70%). Recrystallizationfrom isopropyl alcohol-isopropyl ether gave 4.0 g of cream coloredneedles, mp 144°-146° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OBr: C, 53.50; H, 4.21; N, 15.60.Found: C, 53.38; H, 4.14; N, 15.57;

EXAMPLE 128N,N-Dipropyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(3.21 g, 0.010 mole), and 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole),in anhydrous tetrahydrofuran (75 ml) was stirred at room temperaturewith a stream of nitrogen bubbling through for 3 hours. The nitrogenflow was stopped and a solution of dipropylamine (1.31 g, 0.013 mole) indry tetrahydrofuran (25 ml) was added. The solution was stirred at roomtemperature under nitrogen for 1 hour. The reaction mixture wasconcentrated in vacuo and the residue triturated in potassiumbicarbonate solution (50 ml) and filtered. The filter cake was washedwith water and recrystallized twice from isopropyl ether-petroleumether, giving 1.26 g (31%) of a white solid, mp 138°-139° C.

Analysis: Calculated for C₂₁ H₂₃ N₄ OF₃ : C, 62.37; H, 5.73; N, 13.85.Found: C, 62.20; H, 5.66; N, 13.84.

EXAMPLE 129N-(Phenylmethyl)-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(3.21 g, 0.010 mole), 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), andanhydrous tetrahydrofuran (75 ml) was stirred at room temperature with astream of nitrogen bubbling through for 3 hours. The nitrogen flow wasstopped and a solution of benzylamine (1.39 g, 0.013 mole) in drytetrahydrofuran (25 ml) was added. The solution was stirred at roomtemperature under nitrogen for 1 hour. The reaction mixture wasconcentrated in vacuo and the residue triturated in potassiumbicarbonate solution (50 ml) and filtered. The filter cake was washedwith water and recrystallized from isopropyl alcohol-isopropyl ether,giving 2.8 g (68%). Recrystallization from isopropyl alcoholisopropylether gave 2.3 g of white flakes, mp 224°-225° C.

Analysis: Calculated for C₂₂ H₁₇ N₄ OF₃ : C, 64.39; H, 4.18; N, 13.65.Found: C, 64.27; H, 4.11; N, 13.51;

EXAMPLE 1302-(4-Bromophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:1.5]

A 0.7-g sample (0.00155 mole) of 2-(4-bromophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide obtained in Example 244,was dissolved in acetonitrile (150 ml), acidified with ethereal hydrogenchloride, and refrigerated overnight with seeding. The solid wascollected by filtration, washed with diethyl ether-acetonitrile, anddried under high vacuum overnight. The solid was sublimed under highvacuum at 70° C. to give 0.47 g (55%) of title compound, 180° C.(effervescence).

Analysis: Calculated for C₂₂ H₂₀ N₅ OBr.2HCl.1.5H₂ O: C, 48.02; H, 4.58;N, 12.73. Found: C 47.88; H, 4.58; N, 12.63.

EXAMPLE 131N-Methyl-N-phenyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (1.91 g, 0.015 mole) wasadded dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.5g, 0.014 mole) and anhydrous dimethylformamide (50 ml). The reactionmixture was heated at 55°-60° C. for 4 hours, cooled, and added dropwiseto a stirred and chilled (5°-10° C.) solution of N-methylaniline (1.60g, 0.015 mole), triethylamine (1.52 g, 0.015 mole), and anhydrousdimethylformamide (50 ml). The reaction mixture was stirred at roomtemperature overnight and then poured into water (300 ml). The mixturewas extracted with methylene chloride (3×50 ml). The combined organicextracts were washed with potassium bicarbonate solution (2×30 ml),water (30 ml), dried over sodium sulfate and concentrated in vacuo.Recrystallization twice from isopropyl ether-petroleum ether gave 1.5 g(24%) of off-white needles, mp 158°-159° C.

Analysis: Calculated for C₂₂ H₁₇ N₄ OF₃ : C, 64.39; H, 4.18; N, 13.65.Found: C, 64.45; H, 4.18; N, 13.58;

EXAMPLE 132N,N-Diethyl-2-[4(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(10.0 g, 0.0312 mole), 1,1'-carbonyldiimidazole (6.1 g, 0.0374 mole),and dry tetrahydrofuran (250 ml) was stirred at room temperature for 3hr with a stream of nitrogen bubbling through it. An additional 6.1 g(0.0374 mole) of 1,1'-carbonyldiimidazole was added, and the suspensionwas stirred at room temperature under nitrogen overnight. The suspensionwas heated at 50° C. for 2 hours and then treated with diethylamine(7.07 g, 0.097 mole) in dry tetrahydrofuran (10 ml). The reactionmixture was heated at 50° C. for 5 hr and allowed to stand at roomtemperature over the weekend. The solvent was evaporated under reducedpressure, the resulting solid was triturated in water (200 ml) andfiltered. The solid was dissolved in hot isopropyl alcohol, treated withcharcoal and filtered while hot. Upon cooling, a solid precipitated. Thesolid was filtered and rinsed with isopropyl ether to give 6.4 g (55%)of white solid, mp. 140.5°-142.5° C.

Analysis: Calculated for C₁₉ H₁₉ N₄ OF₃ : C, 60.63; H, 5.09; N, 14.88.Found: C, 60.77; H, 5.09; N, 14.88.

EXAMPLE 133N-Methyl-N-(phenylmethyl)-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

Under nitrogen bubbling, a mixture of2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(3.21 g, 0.01 mole) and 1,1'-carbonyldiimidazole (1.62 g, 0.01 mole) in150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs.N-methylbenzylamine (1.33 g, 0.011 mole) was added, and the reactionmixture was allowed to stir at room temperature for 1 hr.

The tetrahydrofuran was evaporated to dryness. The residue wastriturated with aqueous potassium bicarbonate, collected by filtration,and washed with water. The solid was recrystallized fromethanol-isopropyl ether to give 2.3 g, then from isopropylalcohol-isopropyl ether-petroleum ether to give 2.0 g which was driedunder high vacuum at 79° C. for 4 hrs, then overnight at roomtemperature. The solid was recrystallized from isopropyl ether-petroleumether and dried overnight under high vacuum at 65° C. The solid wastriturated with isopropyl ether-petroleum ether, collected byfiltration, and dried under high vacuum at room temperature overnight togive 1.5 g (35%) of title compound, mp 125.5°-127° C.

Analysis: Calculated for C₂₃ H₁₉ N₄ OF₃.1/2H₂ O: C, 63.74; H, 4.65; N,12.93. Found: C, 63.43; H, 4.35; N, 12.86.

EXAMPLE 134N-[Bis(1-methylethyl)]-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g,0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150ml of tetrahydrofuran was stirred at room temperature for 2 hrs. Thedi-isopropylamine (2.02 g, 0.02 mole) was added, and the reactionmixture was allowed to stir at room temperature overnight. The reactionmixture was heated at 60° C. for 8 hrs.

The tetrahydrofuran was evaporated to dryness, and the residue waspartitioned between methylene chloride and dilute sodium bicarbonate.The aqueous layer was separated and extracted with methylene chloride(2×). The combined methylene chloride layers were extracted with waterand dried over magnesium sulfate. The filtrate was evaporated to asolid, which was dried under high vacuum overnight. The solid wasrecrystallized twice from isopropyl alcohol-water, collected byfiltration, washed with water, and dried under high vacuum overnight togive 0.8 g (12.4%) of title compound, mp 218°-20° C.

Analysis: Calculated for C₂₀ H₂₃ N₄ OCl: C, 64.77; H, 6.25; N, 15.11.Found: C, 64.26; H, 6.23; N, 14.98;

EXAMPLE 1352-(3-Chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

Under nitrogen bubbling, a mixture of2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g,0.0138 mole) and 1,1'-carbonyldiimidazole (2.24 g, 0.0138 mole) in 150ml of tetrahydrofuran was stirred at room temperature for 4 hrs. Asolution of dimethylamine in tetrahydrofuran (42 ml of 0.5M solution)was added, and the reaction mixture was allowed to stir at roomtemperature for 1/2 hr.

The tetrahydrofuran was evaporated to dryness, and the residue waspartitioned between water and ethyl acetate. The water layer wasextracted with ethyl acetate (2×). The combined ethyl acetate layerswere extracted with water (25 ml), dried over magnesium sulfate, andevaporated to dryness. The solid was dissolved in isopropyl alcohol andacidified with ethanolic hydrogen chloride. The solution was dilutedfirst with isopropyl ether, then with tetrahydrofuran to initiatecrystallization. The solid was collected, recrystallized fromtetrahydrofuran-isopropyl alcohol, and dried under high vacuum at 65° C.for 3 hrs, then at room temperature overnight. The hydrochloride saltwas added to water, which converted it to the crystalline free base,which was collected by filtration, washed with water and dried underhigh vacuum for 2 days to give 1.0 g (22%) of crystals, mp 68°-70° C.(melted and resolidified), 107° C. (melted and resolidified), 125°-26°C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OCl.1/2H₂ O: C, 59.35; H, 4.98; N,17.30. Found: C, 59.72; H, 4.94; N, 17.43.

EXAMPLE 136N,N-Dibutyl-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(3.21 g, 0.01 mole) and 1,1'-carbonyldiimidazole (1.62 g, 0.01 mole) in100 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Thedi-n-butylamine (1.68 g, 0.013 mole) was added, and the reaction wasallowed to stir at room temperature for 1 hr.

The tetrahydrofuran was evaporated to dryness. The residue wastriturated with aqueous potassium bicarbonate solution (50 ml),collected by filtration, and washed with water. The solid was trituratedwith diethyl ether, collected by filtration, and crystallized fromisopropyl ether-isopropyl alcohol. The solid was recrystallized firstfrom isopropyl ether-petroleum ether to give 0.81 g, followed byisopropyl alcohol-water to give 0.56 g (13%) after drying under highvacuum for 2 days, mp 116°-117.5° C.

Analysis: Calculated for C₂₃ H₂₇ N₄ OF₃ : C, 63.88; H, 6.29; N, 12.95.Found: C, 63.76; H, 6.25; N, 12.91.

EXAMPLE 1372-(3-Chlorophenyl)-N-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (2.38 g, 0.019 mole) wasadded slowly dropwise to a stirred and chilled (15°-20° C.) solution of2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.70 g,0.016 mole) in 50 ml of dimethylformamide. The reaction mixture wasstirred at ambient temperature for 1/2 hr., then warmed to 60°-65° C.for 5 hrs. This acylchloride solution was added dropwise under nitrogento a stirred and chilled (15°-20° C.) solution of 2-aminopyridine (1.76g, 0.019 mole), triethylamine (1.89 g, 0.019 mole), and 30 ml ofdimethylformamide. The reaction mixture was stirred at room temperatureover the weekend. The reaction mixture was poured into 400 ml of icewater and extracted with ethyl acetate (3×). The ethyl acetate layerswere washed with 5% potassium hydroxide (2×50 ml), water (2×50 ml),dried, and filtered. The residue was treated with isopropyl alcohol andexcess ethereal hydrogen chloride to give solid which was recrystallizedtwice from isopropyl alcohol-isopropyl ether and once from isopropylalcohol. The solid was collected by filtration, washed with coldisopropyl alcohol, then isopropyl alcohol-water, and dried under highvacuum for 2 days to give 0.92 g (15.8%) of title compound, mp 165°-66°C.

Analysis: Calculated for C₁₉ H₁₄ N₅ OCl: C, 62.73; H, 3.88; N, 19.25.Found: C, 62.53; H, 3.88; N, 19.08.

EXAMPLE 1382-(4-Chlorophenyl)-N-methyl-N-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen atmosphere, oxalyl chloride (2.21 g, 0.0174 mole) wasadded slowly dropwise to a stirred and chilled (˜10° C.) suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g,0.0174 mole) in 75 ml of dimethylformamide. After the addition wascomplete, the reaction was heated at 60° C. for 5 hrs. This acylchloridesolution was added dropwise to a stirred and cooled (˜10° C.) solutionof N-methylaniline (2.02 g, 0.019 mole), triethylamine (1.88 g, 0.019mole), and 74 ml of dimethylformamide. The reaction was stirred at roomtemperature overnight. The reaction mixture was poured into 200 ml ofwater and diluted with water until the cloud point. The mixture wasseeded and refrigerated overnight. The solid was collected by filtrationand dried under high vacuum. The solid was suspended in dilute sodiumbicarbonate, collected by filtration, washed with water, and dried underhigh vacuum at 50° C. The solid was recrystallized from isopropylalcohol-water, collected by filtration, washed with water, and driedunder high vacuum first at 56° C., then at 98° C. for 2 days to give 3.0g (45.7%) of crystals, mp 170°-171° C.

Analysis: Calculated for C₂₁ H₁₇ N₄ OCl: C, 66.93; H, 4.55; N, 14.87Found: C, 66.57; H, 4.56; N, 14.81.

EXAMPLE 1392-(4-Chlorophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (2.21 g, 0.0174 mole) wasadded slowly dropwise to a stirred and cooled (0°-10° C.) suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g,0.0174 mole) in 50 ml of dimethylformamide. After the addition wascomplete, the reaction solution was heated at 60° C. for 5 hrs. Thisacylchloride solution was added dropwise to a stirred and cooled (<10°C.) suspension of N,N-dimethyl-1,4-phenylenediamine dihydrochloride(3.64 g. 0.0174 mole), triethylamine (5.27 g, 0.052 mole), and 75 ml ofdimethylformamide. The reaction mixture was stirred at room temperatureovernight. The reaction mixture was poured into 1800 ml of water andrefrigerated overnight. The solid was collected by filtration and dried.The solid was recrystallized twice from isopropyl alcohol, collected byfiltration, washed with water, and dried under high vacuum at 98° C.overnight to give 0.9 g (12.7%) of crystals, mp 245°-246° C.

Analysis: Calculated for C₂₂ H₂₀ N₅ OCl: C, 65.10; H, 4.97; N, 17.25.Found: C, 64.81; H, 4.98; N, 17.24.

EXAMPLE 1402-(4-Methoxyphenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-methoxyphenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g,0.0148 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 mlof tetrahydrofuran was stirred at room temperature for 31/2 hrs. Asolution of dimethylamine in tetrahydrofuran (60 ml of 0.5M) was added,and the reaction was allowed to stir at room temperature overnight.

The tetrahydrofuran was evaporated to dryness, and the residue wastreated with water. The solid was collected by filtration, washed withwater, and dried under high vacuum overnight. The solid wasrecrystallized from isopropyl alcohol, collected by filtration, washedwith water, and dried under high vacuum at 70° C. over 2 days to give1.16 g (25.3%) of crystals, mp 156°-58° C.

Analysis: Calculated for C₁₇ H₁₈ N₄ O₂ : C, 65.79; H, 5.85; N, 18.05.Found: C, 65.66; H, 5.84; N, 17.98;

EXAMPLE 141 2-(3,4-Dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid ethyl ester

A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl]glycine ethylester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heated atreflux for 11/2 hr. The material crystallized upon cooling. A smallportion of the solid was collected by filtration, washed with water, anddried under high vacuum. The solid was recrystallized from ethanol withrefrigeration, collected by filtration, washed with ethanol/watermixture, and dried under high vacuum at 70° C. over 2 days to give 2.0g, mp 141°-42° C.

Analysis: Calculated for C₁₆ H₁₃ N₃ O₂ Cl₂ : C, 54.88; H, 3.74 N, 12.00.Found: C, 54.59; H, 3.75; N, 11.90.

EXAMPLE 1424-[[[(3-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]acetyl]amino]butanoicacid hydrate [1:0.5]

A mixture of4-[[(2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-yl]acetyl]amino]butanoicacid ethyl ester (2.4 g, 0.006 mole) and potassium hydroxide (0.5 g) in100 ml of ethanol was heated at reflux for 2 hrs. The reaction mixturewas evaporated to dryness. The residue was dissolved in water, filtered,and the filtrate was acidified with acetic acid. The precipitate, whichhad formed, was collected by filtration, washed with water, and dried.The solid was recrystallized from ethanol-water, collected byfiltration, washed with water, and dried under high vacuum at 78° C.over 2 days to give 0.93 g (42%), mp 207°-8° C.

Analysis: Calculated for C₁₈ H₁₇ N₄ O₃ Cl.1/2H₂ O: C, 56.62; H, 4.75; N,14.67. Found: C, 56.87; H, 4.71; N, 14.61;

EXAMPLE 1432-(4-Methoxyphenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g,0.015 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 mlof tetrahydrofuran was stirred at room temperature for 3 hrs. Thedipropylamine (3.04 g, 0.03 mole) was added and the reaction mixture wasallowed to stir at room temperature overnight, then heated at reflux for8 hrs. The reaction mixture was filtered and the filtrate was evaporatedto dryness, then placed under high vacuum over the weekend. The residuewas treated with water, and dried under high vacuum. The solid wasdissolved in 100 ml of isopropyl alcohol, filtered, and the filtrateconcentrated to 50 ml. The filtrate was diluted with water, seeded, andplaced in a freezer overnight. The solid was collected by filtration,washed with water, and dried under high vacuum at 50°-60° C. overnightto give 1.8 g (33%) of title compound, mp 127°-29° C.

Analysis: Calculated for C₂₁ H₂₆ N₄ O₂ : C, 68.83; H, 7.15; N, 15.29.Found: C, 68.74; H, 7.15; N, 15.18.

EXAMPLE 1442-(4-Methoxyphenyl)-3-[2-oxo-2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

Under nitrogen bubbling, a mixture of2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine -3-acetic acid (4.2 g,0.015 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 mlof tetrahydrofuran was stirred at room temperature for 3 hrs. Then,under nitrogen atmosphere, piperidine (1.92 g, 0.022 mole) was added andthe reaction mixture was allowed to stir at room temperature overnight.The reaction mixture was filtered and the filtrate was evaporated todryness, then placed under high vacuum for 3-4 hrs. The residue wastreated with water and solid was collected by filtration, washed withwater, and dried under high vacuum at 50°-60° C. overnight. The solidwas recrystallized from isopropyl alcohol with refrigeration overnight.The solid was collected by filtration, washed with cold isopropylalcohol and water, and dried under high vacuum at 50°-60° C. overnightto give 3.21 g (62%) of title compound, mp 153°-55° C.

Analysis: Calculated for C₂₀ H₂₂ N₄ O₂ : C, 68.55; H, 6.33; N, 15.99.Found: C, 68.53; H, 6.34; N, 16.00.

EXAMPLE 145N,N-Diethyl-2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

Under nitrogen bubbling, a mixture of2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g,0.015 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 150 mlof tetrahydrofuran was stirred at room temperature for 3 hrs. Thediethylamine (2.19 g, 0.03 mole) was added and the reaction mixture wasallowed to stir at room temperature overnight, then heated at reflux for3 hrs. The tetrahydrofuran was evaporated to dryness. The residue wastreated with hot water, filtered through a Celite pad, and allowed tocrystallize upon cooling. The solid was collected by filtration, washedwith water, and dried under high vacuum at 50°-60° C. overnight to give1.0 g, mp (softens at 55° C., resolidified) 133°-35° C. Total yield in 2crops was 1.9 g (38%).

Analysis: Calculated for C₁₉ H₂₂ N₄ O₂.0.5H₂ O: C, 65.69; H, 6.67; N,16.13. Found: C, 65.48; H, 6.43; N, 16.13.

EXAMPLE 1462-(3,4-Dichlorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

Under nitrogen bubbling, a mixture of2-3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g,0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 120 mlof tetrahydrofuran was stirred at room temperature for 31/2 hrs. Then,under nitrogen atmosphere, dipropylamine (2.43 g, 0.024 mole) was addedat room temperature and the reaction mixture was heated at reflux for 6hrs. The reaction mixture was filtered, and the filtrate was evaporatedto dryness. The residue was treated with water and refrigerated. Thesolid was collected by filtration, washed with water, and dried underhigh vacuum at 50°-60° C. overnight. The solid was recrystallized fromisopropyl alcohol-water, collected, washed with water, and dried underhigh vacuum at 50°-60 ° C. overnight. Two crops gave 1.9 g (43%) ofcrystals, mp 122°-123° C.

Analysis: Calculated for C₂₀ H₂₂ N₄ OCl₂.0.5H₂ O: C, 57.98; H, 5.60; N,13.52. Found: C, 57.81; H, 5.34; N, 13.54.

EXAMPLE 1472-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

The solid N-[3-[(4-trifluoromethylbenzoyl)amino]-2-pyridinyl] glycineethyl ester (5.0 g, 0.014 mole) was heated in a siliconoil bath at 240°C. for 5 min. The residue was sublimed at 140° C. under high vacuum togive a white solid, 0.7 g (15%), mp 147°-48° C.

Analysis: Calculated for C₁₇ H₁₄ N₃ O₂ F₃ : C, 58.45; H, 4.04; N, 12.03Found: C, 58.43; H, 3.98; N, 12.09.

EXAMPLE 1482-(3-Bromophenyl)-3-[2-oxo-2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

Under nitrogen bubbling, a mixture of2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml oftetrahydrofuran was stirred at room temperature for 4 hrs. Thepiperidine (2.55 g, 0.03 mole) was added and the reaction mixture wasallowed to stir at room temperature overnight. The reaction mixture wasfiltered and the filtrate was evaporated to dryness, then placed underhigh vacuum for 3 hrs. The solid was treated with water, collected byfiltration, washed with water, and dried at 50° C. under high vacuumover the weekend to give 3.93 g (66%) of title compound, mp 157°-58° C.

Analysis: Calculated for C₁₉ H₁₉ N₄ OBr: C, 57.15; H, 4.80; N, 14.03.Found: C, 56.98; H, 4.76; N, 14.00.

EXAMPLE 1492-(3-Bromophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(3-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.98 g, 0.015mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 120 ml oftetrahydrofuran was stirred at room temperature for 4 hrs. Thedi-n-propylamine (3.04 g, 0.03 mole) was added and the reaction mixturewas heated at reflux for (65° C.) for 8-9 hrs. The reaction mixture wasfiltered and the filtrate was evaporated to an oil, which was placedunder high vacuum for 3 hrs. The solid residue was treated with water,collected by filtration, washed with water, and dried under high vacuum.The solid was recrystallized from isopropyl alcohol-water, collected byfiltration, washed with water, and dried under high vacuum to give 3.2 g(52%), mp 125°-27° C.

Analysis: Calculated for C₂₀ H₂₃ N₄ OBr: C, 57.84; H, 5.58; N, 13.49.Found: C, 57.89; H, 5.57; N, 13.48.

EXAMPLE 1502-(3-Chlorophenyl)-N-methyl-N-[3-(4-methyl-1-piperazinyl)propyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.38 g,0.008 mole) and 1,1'-carbonyldiimidazole (1.34 g, 0.008 mole) wasstirred at room temperature for 3 hours. TheN,4-dimethyl-1piperazinepropanamine (1.42 g, 0.008 mole) was added andthe reaction mixture was allowed to stir at room temperature for 2hours. The reaction mixture was evaporated to dryness. The residue waspartitioned between methylene chloride and aqueous potassiumbicarbonate. The aqueous layer was separated and extracted withmethylene chloride. The methylene chloride layers were combined,extracted with aqueous potassium bicarbonate and water and dried oversodium sulfate. The filtrate was evaporated and the solid residue wasrecrystallized as a fumarate salt from ethyl alcohol-isopropyl ether.Recrystallization from isopropyl alcohol-acetonitrile-isopropyl etherdid not improve the analysis. The solid was converted to the free base.The free base was treated with boiling hexanes and allowed to cool toroom temperature. The solid was collected by filtration, washed withhexane, and dried under high vacuum overnight to give 0.7 g of titlecompound, mp 114°-17° C.

Analysis: Calculated for C₂₃ H₂₉ N₆ OCl: C, 62.65; H, 6.63; N, 19.06.Found: C, 62.56; H, 6.61; N, 18.70.

EXAMPLE 1512-(4-Chlorophenyl)-N-(2-methoxyethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.37 g,0.015 mole) and 1,1'-carbonyldiimidazole (2.59 g, 0.016 mole) in 150 mlof tetrahydrofuran was stirred at room temperature for 4 hrs.2-Methoxyethylamine (1.71 g, 0.023 mole) was added and the reactionmixture was allowed to stir at room temperature overnight.

The tetrahydrofuran was evaporated to dryness and the residue was placedunder high vacuum overnight. The solid was recrystallized from hotisopropyl alcohol. The solid was collected by filtration, washed withwater, and dried under high vacuum at 50° C. overnight to give 4.0 g (76%) of title compound, mp 180°-81° C.

Analysis: Calculated for C₁₇ H₁₇ N₄ O₂ Cl: C, 59.22; H, 4.97; N, 16.25.Found: C, 59.24; H, 4.97; N, 16.32;

EXAMPLE 1522-(3,4-Dichlorophenyl)-3-[2-oxo-2-(1-piperidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

Under nitrogen bubbling, a mixture of2-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g,0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 150 mlof tetrahydrofuran was stirred at room temperature for 4 hrs. Piperidine(1.87 g, 0.022 mole) was added and the reaction was allowed to stir atroom temperature overnight.

The reaction mixture was filtered and the filtrate was evaporated todryness, then placed under high vacuum. The solid was recrystallizedfrom isopropyl alcohol, collected by filtration, washed with water, anddried under high vacuum to give 2.58 g (60.2%) of title compound, mp194°-96° C.

Analysis: Calculated for C₁₉ H₁₈ N₄ OCl₂ : C, 58.62; H, 4.66; N, 14.39.Found: C, 58.28; H, 4.58; N, 14.35.

EXAMPLE 1532-(3,4-Dichlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:2]

Under nitrogen bubbling, a mixture of2-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g,0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 150 mlof tetrahydrofuran was stirred at room temperature for 2 hrs, thenheated at 60°-65° C. for 2 hrs. N,N-Dimethylaminoethylamine (1.06 g,0.012 mole) was added and the reaction mixture was allowed to stir atroom temperature. The reaction mixture was filtered and the filtrate wasevaporated to dryness, then placed under high vacuum overnight. Thesolid was treated with ice water, collected by filtration, washed withwater, and dried under high vacuum at 50° C. overnight. The solid wasdissolved in acetone and acidified with ethanolic hydrogen chloride. Thecrystalline precipitate was collected by filtration, washed with coldacetone, and dried under high vacuum to give 3.61 g. The solid wasdissolved in 1.2 liters of acetone and concentrated to 600 ml toinitiate crystallization. The solid was collected by filtration, washedwith acetone, and dried under high vacuum overnight at 50° C. to give1.9 g of title compound, mp 120°-122° C.

Analysis: Calculated for C₁₈ H₁₉ N₅ OCl₂.2HCl: C, 46.47; H, 4.55; N,15.05; Found; C, 46.60; H, 4.86; N, 14.87.

EXAMPLE 1542-(4-Chlorophenyl)-N,N-diphenyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.0137 mole) wasadded dropwise, slowly, to a stirred and chilled (10° C.) solution of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013mole) in anhydrous dimethylformamide (50 ml). The reaction mixture washeated at 60° C. for 4 hr under nitrogen, cooled and added dropwise to astirred and chilled (10° C.) solution of diphenylamine (2.37 g, 0.014mole) and triethylamine (1.42 g, 0.014 mole) in anhydrousdimethylformamide (75 ml). The reaction mixture was stirred at roomtemperature overnight and then poured into water (400 ml). The mixturewas extracted with ethyl acetate (2×75 ml). The aqueous layer wassaturated with sodium chloride and extracted again with ethyl acetate(75 ml). The combined organic layers were washed with 5% potassiumhydroxide solution (2×50 ml), water (50 ml) and saturated sodiumchloride solution (50 ml). The combined layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure to give 4.0 gof an oil (70%). The oil was crystallized from isopropyl ether-isopropylalcohol to give 2.2 g (39%) of a white solid, mp. 176°-178° C.

Analysis: Calculated for C₂₆ H₁₉ N₄ OCl: C, 71.15; H, 4.36; N, 12.76.Found: C, 70.87; H, 4.38; N, 12.68;

EXAMPLE 155N-[2-Dimethylamino)ethyl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.0156 mole) 1,1'-carbonyldiimidazole (3.0 g, 0.0185 mole) anddry tetrahydrofuran (125 ml) was stirred at room temperature for 2 hourswith nitrogen bubbling through it. The reaction mixture was then heatedat 50° C. under nitrogen for 2 hours. The solution was cooled and asolution of N,N-dimethylethylenediamine (4.2 g, 0.047 mole) intetrahydrofuran (5 ml) was added. The reaction mixture was stirred atroom temperature overnight under nitrogen and evaporated under reducedpressure. The residue was triturated in water, and the solid wascollected by filtration, washed once with water, twice with 5% potassiumhydroxide solution and then twice again with water to yield 3.0 g (49%)of product. A 0.7-g sample of the solid was dissolved in hot isopropylether with a little isopropyl alcohol added to aid solubility, filtered,and cooled to room temperature to yield 0.4 g of a white solid, mp196°-197° C.

Analysis: Calculated for C₁₉ H₂₀ N₅ F₃ O₁ : C, 58.31; H, 5.15; N, 17.89.Found: C, 58.62; H, 5.18; N, 18.11.

EXAMPLE 156N-[2-(Dimethylamino)ethyl]-2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:2]

A solution of 2.3 g ofN-[2-(dimethylamino)ethyl]-2-]4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamidein hot isopropyl alcohol was acidified with concentrated hydrochloricacid. The solvents were evaporated under reduced pressure and theresidue redissolved in hot isopropyl alcohol and methanol, filtered, andwhile still hot, isopropyl ether was added to the cloud point. Solidprecipitated upon cooling to room temperature. The solid was collectedby filtration to give 1.8 g of a white solid, mp 230°-234° C.

Analysis: Calculated for C₁₉ H₂₂ N₅ F₃ O₁ Cl₂ : C, 49.15; H, 4.78; H,15.08. Found: C, 48.83; H, 4.96; N, 14.69.

EXAMPLE 1572-(4-Chlorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-propanamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoicacid 5.0 g, 0.0166 mole) 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole)and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1hour with nitrogen bubbling through it. The reaction mixture was thenheated at reflux for 1 hour under nitrogen during which a solutionformed. A solution of dipropylamine (5.04 g, 0.050 mole) intetrahydrofuran (7 ml) was added and the reaction mixture was heated at50° C. overnight under nitrogen. The reaction mixture was evaporatedunder reduced pressure and the residue was partitioned between water andethyl acetate (100 ml of each). The two layer mixture was filtered toremove an insoluble solid and the layers were separated. The aqueouslayer was re-extracted once with ethyl acetate and the combined organiclayers were washed once with a 5% potassium hydroxide solution (100 ml),dried over sodium sulfate, filtered, and evaporated to a residueweighing 8.9 g. The residue was dissolved in hot isopropyl alcohol,filtered, cooled to room temperature, and water was added. Solid formedwhich was collected by filtration to give 4.84 g (76%) of a white solid,after drying under vacuum overnight, mp 104°-105.5° C.

Analysis: Calculated for C₂₁ H₂₅ N₄ O₁ Cl₁ : C, 65.53; H, 6.55; N,14.56. Found: C, 65.35; H, 6.59; N, 14.53;

2-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-propanamidehydrochloride [1:2]

A solution of 3.9 g of crude2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-propanamidein hot isopropyl alcohol-methanol was filtered and acidified withethereal hydrogen chloride. Isopropyl ether was added to precipitate asolid. The entire mixture was evaporated under reduced pressure,redissolved in hot isopropyl alcohol and precipitated with isopropylether. The solid was collected by filtration and dried under highvacuum. The solid melted. The resulting glass was combined with a secondcrop of solid and recrystallized from isopropyl alcohol/acetone/diethylether to give a white solid which after drying under high vacuum at roomtemperature and then at 50° C. gave a white solid, mp 202°-205° C.

Analysis: Calculated for C₁₉ H₂₄ N₅ O₁ Cl_(3:) C, 51.31; H, 5.44; N,15.74. Found: C, 51.14; H, 5.48; N, 15.78.

EXAMPLE 1592-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-propanamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoicacid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor 2 hours with nitrogen bubbling through it. The reaction mixture wasthen heated at 55° C. for 2 hours under nitrogen and cooled to roomtemperature. A solution of N,N-dimethylethylenediamine (4.41 g, 0.050mole) in tetrahydrofuran (5.5 ml) was added and the reaction mixture wasstirred at room temperature under nitrogen over the weekend. Thereaction mixture was evaporated to a white solid and triturated withwater (100 ml). The solid was collected by filtration, rinsed once witha 5% potassium hydroxide solution, and washed twice more with water togive 4.9 g of a white solid (79%). A second crop of white solid wasobtained from the mother liquor of the above solid. The second crop wasdried under high vacuum at 70° C. to give a white solid, mp 141.5°-143°C.

Analysis: Calculated for C₁₉ H₂₂ N₅ O₁ Cl₁ : C, 61.37; H, 5.96; N,18.83. Found: C, 61.64; H, 6.04; N, 19.12.

EXAMPLE 1603-[2-(1-Azetidinyl)-2-oxoethyl]-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (6.72 g, 0.0234 mole), 1,1'-carbonyldiimidazole (3.78 g, 0.0234mole) and dry tetrahydrofuran (85 ml) was stirred at room temperaturefor 2 hours with nitrogen bubbling through and was then stirred at roomtemperature under nitrogen overnight. A solution of azetidine (2.0 g,0.0350 mole) in tetrahydrofuran (10 ml) was added. The resultingsuspension was stirred at room temperature under nitrogen for 3.5 hours,evaporated to a white solid, triturated with water (75 ml), the solidfiltered and rinsed twice with water. The solid was dissolved in hotisopropyl alcohol, filtered, and cooled to room temperature to yield awhite solid. The solid was collected by filtration, rinsed once withisopropyl alcohol, twice with isopropyl ether and dried under highvacuum at room temperature to give 5.34 g (70%) of a white solid, mp195.5°-197° C.

Analysis: Calculated for C₁₇ H₁₅ N₄ O₁ Cl₁ : C, 62.48; H, 4.63; N,17.14. Found: C, 62.29; H, 4.57; N, 17.23.

EXAMPLE 1612-(4-Chlorophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-propanamidehydrochloride [1:2]

A solution of 0.9 g of2-(4-chlorophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-propanamide(obtained in Example 245), in hot isopropyl alcohol was acidified withethereal hydrogen chloride. Isopropyl ether was added and a pink solidformed. The solid was collected by filtration, rinsed with isopropylether and then recrystallized from isopropyl alcoholisopropyl ether togive 0.81 g of a lavender solid. After drying at high vacuum, mp215.5°-217° C.

Analysis: Calculated for C₂₃ H₂₄ N₅ O₁ Cl₃ : C, 56.05; H, 4.91; N,14.21. Found: C, 55.94; H, 5.09; N, 13.94.

EXAMPLE 1622-(4-Chlorophenyl)-N-[2-(diethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (6.0 g, 0.021 mole), 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole)and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3hours with nitrogen bubbling through it. A solution ofN,N-diethylethylenediamine (7.32 g, 0.063 mole) in tetrahydrofuran (10ml) was added and the reaction mixture was stirred at room temperatureunder nitrogen overnight. The reaction mixture was evaporated to asolid. The solid was triturated with water (50 ml), filtered, and thefilter cake was rinsed twice with water, twice with a 5% potassiumhydroxide solution and twice with water. The resulting solid wasdissolved in hot isopropyl alcohol, filtered hot and cooled to roomtemperature. Addition of water caused a white solid to form. The solidwas collected by filtration and rinsed with water to give 4.21 g (52%)of a white solid A 1.0-g sample of the solid was dried under high vacuumat room temperature to give a white solid, mp 142°-143° C.

Analysis: Calculated for C₂₀ H₂₄ N₅ O₁ Cl₁ : C, 62.25; H, 6.27; N,18.15. Found: C, 62.15; H, 6.28; N, 18.30;

EXAMPLE 1632-(4-Chlorophenyl)-N-[2-(diethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:0.5]

A solution of crude2-(4-chlorophenyl-N-[2-(diethylamino)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide(3.21 g, 0.0112 mole) in hot isopropyl alcohol was treated with etherealhydrogen chloride until acidic. The solution was evaporated to dryness,the residue dissolved in hot isopropyl alcohol and the solution wasfiltered while hot. Solid precipitated upon cooling to room temperature.Isopropyl ether was added and the solid was collected by filtration andrinsed with isopropyl ether. The solid was dried under high vacuum togive 4.4 g (84%) of title compound, mp. 193°-196° C.

Analysis: Calculated for C₂₀ H₂₇ N₅ O₁.5 Cl₃ : C, 51.35; H, 5.82; N,14.96. Found: C, 51.23; H, 5.72; N, 14.94.

EXAMPLE 1642-(4-Chlorophenyl-N-[3-(diethylamino)propyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor 2 hours with nitrogen bubbling through it. A solution of3-diethylaminopropylamine (6.8 g, 0.0522 mole) in tetrahydrofuran (10ml) was added and the reaction mixture was stirred at room temperatureovernight under nitrogen. The reaction mixture was evaporated underreduced pressure to give a white solid. The solid was triturated withwater (50 ml), filtered and rinsed twice with water, twice with a 5%potassium hydroxide solution and twice with water to yield a whitesolid. The solid was dissolved in hot isopropyl alcohol and filtered.Addition of water and cooling to room temperature gave a white solidwhich was collected by filtration and rinsed with water to give 4.33 g(61%) of a solid. A 1.0-g sample of the solid was dried at high vacuum,mp 172° -174° C.

Analysis: Calculated for C₂₁ H₂₆ N₅ O₁ Cl₁ : C, 63.07; H, 6.55; N,17.51. Found: C, 63.11; H, 6.58; N, 17.74.

EXAMPLE 1652-(4-Chlorophenyl)-N-[3-(diethylamino)propyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:2]

Approximately 5.7 g of crude2-(4-chlorophenyl)-N-[3-(diethylamino)propyl]-3H-imidazo[4,5-b]pyridine-3-acetamidewas dissolved in hot isopropyl alcohol and acidified with etherealhydrogen chloride. The solvents were removed under reduced pressure. Theresidue was redissolved in hot isopropyl alcohol and cooled to roomtemperature while a solid formed. The solid was collected by filtration,rinsed with an isopropyl alcohol-isopropyl ether solution and finallyrinsed with isopropyl ether. Drying under high vacuum gave a white solidweighing 5.0 g, mp 173°-177° C.

Analysis: Calculated for C₂₁ H₂₈ N₅ O₁ Cl₃ : C, 53.34; H, 5.97; N,14.81. Found: C, 52.97; H, 5.98; N, 14.80.

EXAMPLE 1662-(4-Chlorophenyl)-N-(4,5-dihydro-2-thiazolyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole) 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole)and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5hours with a stream of nitrogen bubbling through it. Solid2-amino-2-thiazoline (2.67 g, 0.0261 mole) was added to the reactionmixture. The resulting suspension was allowed to stir at roomtemperature overnight. The solvent was evaporated under reduced pressureto give a white solid. The solid was triturated in water (200 ml),filtered, and the filter cake was rinsed twice more with water. Theresulting solid was heated in boiling isopropyl alcohol to dissolve mostof it, filtered while hot, and cooled to room temperature. A whiteprecipitate formed. Water was added, and the white solid was filteredand rinsed once with isopropyl alcohol and twice with isopropyl ether. A1.0-g sample of the resulting 3.3 g of white solid was dried at highvacuum to give 0.6 g (29%) of title compound, mp. 227°-229° C.

Analysis: Calculated for C₁₇ H₁₄ N₅ SOCl: C, 54.91; H, 3.80; N, 18.83.Found: C, 54.94; H, 3.74; N, 18.85.

EXAMPLE 1672-(4-Chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-propanamidehydrochloride [1:1]

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoicacid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor one hour with nitrogen bubbling through it and then refluxed for onehour under a nitrogen atmosphere. The solution which had formed wascooled and a solution of dimethylamine in tetrahydrofuran (21.4 ml of2.3M solution, 0.05 mole) was added. The reaction mixture was stirred atroom temperature under nitrogen overnight. The solvent was removed underreduced pressure and the resulting oil was partitioned between water(100 ml) and ethyl acetate (100 ml). The layers were separated and thesuspended solid was removed by filtration. The aqueous layer wasextracted once more with ethyl acetate (100 ml) and the combined organiclayer was washed once with a 5% potassium hydroxide solution (100 ml).The organic layer was dried over sodium sulfate, filtered, andevaporated under reduced pressure to give 6.3 g of crude product.Attempts to crystallize the pure free base failed (due to imidazolecontamination and trapping of solvents by the solid). The impureproduct, after triturations in water to remove imidazole, was dissolvedin hot isopropyl alcohol, filtered while hot and acidified with hydrogenchloride in isopropyl alcohol. Isopropyl ether was added to precipitatethe solid. Filtration and drying under high vacuum gave 1.84 g of thetitle compound, mp. 203°-205° C.

Analysis: Calculated for C₁₇ H₁₈ N₄ OCl₂ : C, 55.90; H, 4.97; N, 15.34.Found: C, 55.89; H, 4.92; N, 15.37;

EXAMPLE 1682-(4-Chlorophenyl)-N-methyl-N-phenyl-3H-imidazo[4,5-b]pyridine-3-propanamidehydrochloride [1:1]

Under nitrogen atmosphere, oxalyl chloride (2.18 g, 0.0172 mole) wasadded dropwise, slowly, to a stirred and chilled (10° C.) suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.0 g,0.0166 mole) in anhydrous dimethylformamide (75 ml). The reactionmixture was stirred at room temperature for 1.5 hours and thenadditional oxalyl chloride (0.73 g, 0.00573 mole) was added. Afterstirring at room temperature for 0.5 hour, the reaction mixture wascooled in ice and methylaniline (1.91 g, 0.0178 mole) was added. Thereaction mixture was stirred at room temperature for 2.25 hours and thenpoured into ice water (400 ml) with stirring. Addition of triethylamine(6 ml) precipitated a solid. The solution was decanted from the gum andthe gum was dissolved in hot isopropyl alcohol, treated with charcoaland filtered hot. Attempts to crystallize the free base failed. Theproduct, in isopropyl alcohol, was treated with hydrogen chloride inisopropyl alcohol until acidic. Addition of isopropyl ether caused a tansolid to precipitate. The solid was filtered, rinsed with isopropylether and dried under high vacuum to give 1.93 g of title compound, mp.178°-183° C.

Analysis: Calculated for C₂₂ H₂₀ N₄ OCl₂ : C, 61.84; H, 4.72; N, 13.11.Found: C, 61.47; H, 4.75; N, 12.84.

EXAMPLE 1692-(4-Chlorophenyl)-3-[2-oxo-2-(3-thiazolidinyl)ethyl]-3H-imidazo[4,5-b]pyridine

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2,82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor 3.5 hours while nitrogen was bubbled through it. Solid thiazolidine(2.33 g, 0.0261 mole) was added and the reaction mixture was stirred at55° C., under nitrogen overnight. The solvent was removed under reducedpressure. The resulting white solid was triturated with water (100 ml),filtered, rinsed with water, twice with 5% potassium hydroxide solutionand twice more with water. The resulting solid was heated in boilingisopropyl alcohol and filtered hot. Upon cooling to room temperature, awhite solid precipitated. The solid was collected by filtration anddried under high vacuum to give 3.08 g (49.4%) of title compound, mp.215°-218° C.

Analysis: Calculated for C₁₇ H₁₅ N₄ OClS: C, 56.90; H, 4.21; N, 15.61.Found: C, 56.72; H, 4.30; N, 15.34.

EXAMPLE 1702-(4-Chlorophenyl)-N-(2-thiazolyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor 3.5 hours with nitrogen bubbling through it. A solution formed, andsolid 2-aminothiazole (2.61 g, 0.0261 mole) was added. The suspensionwas stirred overnight at room temperature under nitrogen. The solventswere evaporated under reduced pressure to give a white solid which wastriturated in water (100 ml), filtered, and the filter cake rinsed withwater, 2 portions of 5% potassium hydroxide solution and 2 additionalportions of water. The white solid was dissolved in hot methanol,filtered hot and allowed to cool to give 2.70 g (42% yield) of whitesolid. The solid was suspended in hot isopropyl alcohol and treated withisopropyl alcohol-hydrogen chloride. A solution formed. Addition ofisopropyl ether and cooling to room temperature gave a white solid. Thissolid was dissolved in hot methanol and isopropyl alcohol, filtered hotand cooled. The resulting solid was dried under high vacuum at 92° C.overnight which caused the hydrogen chloride to be driven off leaving1.0 g of title compound, mp >260° C.

Analysis: Calculated for C₁₇ H₁₂ N₅ OClS: C, 55.21; H, 3.27; N, 18.94.Found: C, 55.11; H, 3.27; N, 18.82;

EXAMPLE 171(S)-2-(4-Chlorophenyl)-N,N,α-trimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of(S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) anddry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hourswith nitrogen bubbling through it. A solution of dimethylamine (2.26 g,0.050 mole) in tetrahydrofuran (20 ml) was added and the reactionmixture was stirred at room temperature under nitrogen overnight. Themixture was evaporated to an oil and partitioned between ethyl acetate(50 ml) and water (50 ml). The layers were separated and the aqueouslayer was re-extracted with ethyl acetate. The combined organic layerswere washed once with water (50 ml), twice with 5% potassium hydroxidesolution (50 ml portions), and once more with water (50 ml). Drying overmagnesium sulfate, treatment with charcoal, filtration and evaporationof the solvents gave a residue which upon recrystallization from hotisopropyl ether and drying under high vacuum gave 3.20 g (59%) of titlecompound, mp 124°-126° C.

Analysis: Calculated for C₁₇ H₁₇ N₄ OCl: C, 62.10; H, 5.21; N, 17.04.Found: C, 62.11; H, 5.21; N, 17.06.

EXAMPLE 172(S)-2-(4-Chlorophenyl)-α-methyl-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of(S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) anddry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hourswith nitrogen bubbling through it. A solution of dipropylamine (5.04 g,0.050 mole) in tetrahydrofuran (7 ml) was added and the solution washeated at 50° C. overnight under nitrogen. The solvents were evaporatedunder reduced pressure and the resulting oil was partitioned betweenethyl acetate (50 ml) and water (50 ml). The layers were separated andthe aqueous layer was re-extracted with ethyl acetate (50 ml). Thecombined organic layers were washed once with water (50 ml) followed bytwo (50 ml) portions of 5% potassium hydroxide solution and then bywater again (50 ml). The organic layer was dried over magnesium sulfate,charcoaled, filtered and evaporated to an oil which was crystallizedfrom hot isopropyl ether. The solid was collected by filtration, anddried under high vacuum at room temperature to give 3.33 g (52%) oftitle compound, mp 96°-99° C.

Analysis: Calculated for C₂₁ H₂₅ N₄ OCl: C, 65.53; H, 6.55; N, 14.56.Found: C, 65.44; H, 6.54; N, 14.56.

EXAMPLE 173(S)-2-(4-Chlorophenyl)-N,α-dimethyl-N-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (2.18 g, 0.0172 mole) wasadded slowly, dropwise, to a stirred and chilled (10° C.) suspension of(S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.0166 mole) in dry dimethylformamide (75 ml). The mixture wasstirred at room temperature for 3 hours, heated at 50° C. for one hourand cooled to room temperature. An additional 0.0057 mole of oxalylchloride was added and the mixture was stirred at room temperature for30 minutes. N-Methylaniline (1.92 g, 0.0179 mole) was added and thereaction mixture was stirred at room temperature under nitrogenovernight. The mixture was poured into 400 ml of ice water andtriethylamine (6 ml) was added. The precipitated solid was collected byfiltration, rinsed with water, redissolved in hot isopropyl alcohol,treated with charcoal, filtered hot and allowed to cool. Addition ofwater caused a solid to form. The solid was collected by filtration,rinsed with water and dried under high vacuum overnight to give 4.2 g(65%) of title compound, mp 174°-177° C.

Analysis: Calculated for C₂₂ H₁₉ N₄ OCl: C, 67.60; H, 4.90; N, 14.33.Found: C, 67.41; H, 4.91; N, 14.24;

EXAMPLE 1742-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole) 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole)and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2hours with nitrogen bubbling through it, during which time a solutionformed. A solution of N,N,N'-trimethylenediamine (3.56 g, 0.0348 mole)in tetrahydrofuran (4.5 ml) was added and the solution was refluxedovernight under a nitrogen atmosphere. The solvents were removed underreduced pressure and the resulting oil was partitioned between water(100 ml) and ethyl acetate (100 ml). The layers were separated, theaqueous layer was re-extracted with ethyl acetate, and the combinedorganic layers were washed once with water, twice with 5% potassiumhydroxide solution and twice with water. The organic layer was driedover sodium sulfate and evaporated under reduced pressure. The residuewas recrystallized from isopropyl ether to give 3.5 g of product. A1.0-g portion was dried at high vacuum overnight to give 0.63 g of titlecompound, mp 120°-122° C.

Analysis: Calculated for C₁₉ H₂₂ N₅ OCl: C, 61.37; H, 5.96; N, 18.83.Found: C, 61.23; H, 5.95; N, 18.82.

EXAMPLE 1752-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride [1:2]

A solution of crude2-(4-chlorophenyl)-N-[2-(dimethylamino)-ethyl]-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide(2.5 g, 0.0067 mole) in hot isopropyl alcohol was treated with hydrogenchloride in isopropyl alcohol until the solution was acidic. Uponaddition of isopropyl ether, solid precipitated. After cooling to roomtemperature, the solid was collected by filtration, rinsed withisopropyl ether, and dried under high vacuum to give 2.23 g (75%) oftitle compound, mp 239°-242° C.

Analysis: Calculated for C₁₉ H₂₄ N₅ OCl₃ : C, 51.31; H, 5.44; N, 15.74.Found: C, 50.99; H, 5.57; N, 15.45.

EXAMPLE 176(S)-2-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of(S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) intetrahydrofuran (100 ml) was stirred at room temperature for two hourswith nitrogen bubbling through it. A solution ofN,N-dimethylethylenediamine (4.41 g, 0.050 mole) in tetrahydrofuran (5.5ml) was added and the reaction mixture was stirred at room temperatureunder nitrogen overnight. The solvents were removed under reducedpressure and the solid was triturated in water (100 ml). The solid wascollected by filtration, rinsed once with water, twice with 5% potassiumhydroxide solution and twice with water. The solid was recrystallizedfrom hot isopropyl ether to give 1.99 g (32%) of a solid. A 0.5-g samplewas dried under high vacuum to give 0.49 g of title compound, mp130°-133° C.

Analysis: Calculated for C₁₉ H₂₂ N₅ OCl: C, 61.37; H, 5.96; H, 18.83.Found: C, 61.36; H, 5.97; N, 18.83.

EXAMPLE 177(S)-2-(4-Chlorophenyl)-N-[2-(dimethylamino)ethyl]-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:0.5]

A solution of crude(S)-2-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide(1.49 g, 0.00335 mole) in hot isopropyl alcohol was treated withhydrogen chloride in isopropyl alcohol until the solution was acidic.Upon addition of isopropyl ether, solid precipitated. After cooling toroom temperature, the solid was collected by filtration, rinsed withisopropyl ether, and dried under high vacuum to give 1.64 g of titlecompound, mp 252°-255° C.

Analysis: Calculated for C₁₉ H₂₅ N₅ O₁.5 Cl₃ : C, 50.29; H, 5.55; N,15.43. Found: C, 50.64; H, 5.58; N, 15.32.

EXAMPLE 1782-(4-Chlorophenyl)-N-methyl-N-(2-propenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor 2 hours with nitrogen bubbling through it. A solution formed. Asolution of N-allylmethylamine (3.71 g, 0.0522 mole) in tetrahydrofuran(5.0 ml) was added and the reaction mixture was stirred at 40°-50° C.overnight under nitrogen. The solvents were removed under reducedpressure and the residue was triturated in water (100 ml). The solid wascollected by filtration, rinsed once with water, twice with 5% potassiumhydroxide solution, and twice again with water. The solid wasrecrystallized from hot isopropyl ether, collected by filtration, rinsedwith isopropyl ether, and dried under high vacuum to give 2.01 g (34%)of title compound, mp 124°-127° C.

Analysis: Calculated for C₁₈ H₁₇ N₄ OCl: C, 63.44; H, 5.03; N, 16.44.Found: C, 63.22; H, 5.00; N, 16.52.

EXAMPLE 1792-(4-Chlorophenyl)-N-(1,2-diethyl-4-pyrazolidinyl)-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:0.5]

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'carbonyldiimidazole (2.82 g, 0.0174 mole)and dry tetrahydrofuran (100 ml) was stirred at room temperature for twohours with nitrogen bubbling through it. A solution of4-amino-1,2-diethyl-pyrazolidine (7.5 g, 0.0522 mole) in tetrahydrofuran(6 ml) was added and the reaction mixture was stirred at roomtemperature overnight under nitrogen. The reaction mixture wasevaporated under reduced pressure to an oil. Water (200 ml) was added,and the resulting suspension was stirred. The solid was collected byfiltration, rinsed twice with water, twice with 5% potassium hydroxidesolution and twice again with water. The solid was dissolved in hotisopropyl alcohol, filtered hot, and acidified with hydrogen chloride inisopropyl alcohol. Isopropyl ether was added to the cloud point, andupon cooling to room temperature, a solid precipitated. The solid wascollected by filtration, rinsed with isopropyl ether, and dried underhigh vacuum to give 4.8 g (56%) of title compound, mp 220° C. (darkens),228°-230° C. (melts).

Analysis: Calculated for C₂₁ H₂₈ N₆ O₁.5 Cl₃ : C, 50.97; H, 5.70; N,16.98. Found: C, 51.05; H, 5.61; N, 16.59.

EXAMPLE 180N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:1]

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor three hours with nitrogen bubbling through it. 3-Aminoquinuclidinedihydrochloride (20.8 g, 0.104 mole) and sodium methoxide (freshlyprepared from 5.28 g of sodium metal in 50 ml of methanol) were stirredat room temperature for one hour. This second suspension was filteredand evaporated to an oil. The oil was extracted into boiling lightpetroleum ether (1500 ml) and the petroleum ether was then removed underreduced pressure to give 6.6 g of 3-aminoquinuclidine. The3-aminoquinuclidine was dissolved in tetrahydrofuran (20 ml) and addedto the solution containing the product resulting from the firstsuspension. The reaction mixture was stirred at room temperature under anitrogen atmosphere overnight.

The solvents were removed under reduced pressure to give a white solidwhich was triturated in water (200 ml), collected by filtration, andrinsed twice with water, twice with 5% potassium hydroxide solution andtwice again with water. The resulting solid was dissolved in hotisopropyl alcohol, filtered hot, and acidified with hydrogen chloride inisopropyl alcohol. Isopropyl ether was added to the cloud point and uponcooling to room temperature, a solid precipitated. The solid wascollected by filtration, rinsed with isopropyl ether and dried underhigh vacuum overnight to give 5.3 g (62%) of title compound, mp240°-245° C.

Analysis: Calculated for C₂₁ H₂₆ N₅ O₂ Cl₃ : C, 51.81; H, 5.38; N,14.38. Found: C, 51.44; H, 5.33; N, 14.16.

EXAMPLE 1812-(4-Chlorophenyl)-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:1]

A solution of crude2-(4-chlorophenyl)-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide(3.96 g, 0.0100 mole) in hot isopropyl alcohol was acidified withhydrogen chloride in isopropyl alcohol. Isopropyl ether was added to thecloud point. Upon cooling to room temperature, a solid precipitated. Thesolid was collected by filtration, rinsed with isopropyl ether, anddried under high vacuum to give 4.2 g (86%) of title compound, mp171°-175° C.

Analysis: Calculated for C₂₁ H₂₈ N₅ O₂ Cl₃ : C, 51.60; H, 5.77; N,14.33. Found: C, 51.38; H, 5.67; N, 14.19.

EXAMPLE 1822-(4-Chlorophenyl)-N-[2-(1-methyl-2-pyrrolidinyl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor two hours with nitrogen bubbling through it. A solution of2-(2-aminoethyl)-1-methylpyrrolidine (5.6 g, 0.0435 mole) intetrahydrofuran (6 ml) was added and the reaction mixture was stirred atroom temperature overnight under a nitrogen atmosphere. The solventswere removed under reduced pressure. The resulting solid was trituratedin water (200 ml), collected by filtration, rinsed twice with water,twice with 5% potassium hydroxide solution and twice again with water.The solid was dissolved in hot isopropyl alcohol, filtered hot, andwater was added. Upon cooling, a solid precipitated. The solid wascollected by filtration and air dried to give 4.46 g (64%) of solid. A0.5-g sample was dried under high vacuum to give 0.40 g of titlecompound, mp 170°-172° C.

Analysis: Calculated for C₂₁ H₂₄ N₅ OCl: C, 63.39; H, 6.08; N, 17.60.Found: C, 63.02; H, 6.03; N, 17.38.

EXAMPLE 1832-(4-Chlorophenyl)-N-[4-(dimethylamino)phenyl]-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole) in dry dimethylformamide (75 ml) was cooled inan ice bath and oxalyl chloride (2.2 g, 0.0172 mole) was added dropwise,with stirring, under nitrogen. The reaction mixture was stirred at roomtemperature for 3.5 hours and then N,N,N'-trimethyl-1,4-benzenediamine(2.9 g, 0.0193 mole) was added dropwise. The reaction mixture wasstirred at room temperature under nitrogen overnight, poured into 400 mlof ice water and made basic with triethylamine (6 ml). The resultingwhite solid was collected by filtration, dissolved in hot isopropylalcohol, treated with charcoal, and filtered while hot. Water was addedto the cloud point and upon cooling, a solid precipitated. The graysolid was collected by filtration and rinsed with water to yield 6.6 g(92%) of product. A 1.0-g sample was dried under high vacuum to give 0.6g of title compound, mp 152°-155° C.

Analysis: Calculated for C₂₃ H₂₂ N₅ OCl: C, 65.79; H, 5.28; N, 16.68.Found: C, 65.79; H, 5.31; N, 16.57.

EXAMPLE 1842-(4-Chlorophenyl)-N-[4-(dimethylamino)phenyl]-N-methyl-3-H-imidazo[4,5-b]pyridine-3-acetamide hydrochloride hydrate [1:2:2.5].

A solution of2-(4-chlorophenyl)-N-[4-(dimethylamino)phenyl]-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide(5.6 g, 0.0133 mole) in hot isopropyl alcohol was acidified withhydrogen chloride in isopropyl alcohol. Isopropyl ether was added toprecipitate a solid. The solid was collected by filtration, rinsed withisopropyl ether, and dried under high vacuum to give 3.74 g (52%) oftitle compound, mp 120°-132° C. (shrinks), 150°-155° C. (melts).

Analysis: Calculated for C₂₃ H₂₉ N₅ O₃.5 Cl₃ : C, 51.36; H, 5.43; N,13.02. Found: C, 51.48; H, 5.10; N, 12.83.

EXAMPLE 1854-[[2-(4-Chlorophenyl)-3-H-imidazo[4,5-b]pyridin-3-yl]acetyl]-1-piperazinecarboxylicacid ethyl ester

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'carbonyldiimidazole (2.82 g, 0.0174mole), and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor two hours with nitrogen bubbling through it. A solution ofethyl-1-piperazine carboxylate (6.9 g, 0.0435 mole) in tetrahydrofuran(6 ml) was added dropwise and the reaction mixture was stirred at 50° C.overnight under nitrogen. The solvents were removed under reducedpressure and the residual oil was triturated in water (100 ml)overnight. The resulting solid was collected by filtration, rinsed withwater, dissolved in hot isopropyl alcohol, and filtered hot. Water wasadded to the cloud point and upon cooling to room temperature, a solidprecipitated, which was collected by filtration, rinsed with water, anddried under high vacuum to give 4.66 g (63%) of title compound, mp184°-186° C.

Analysis: Calculated for C₂₁ H₂₂ N₅ O₃ Cl: C, 58.95; H, 5.18; N, 16.37.Found: C, 58.87; H, 5.14; N, 16.32.

EXAMPLE 1862-(4-Chlorophenyl)-N,N-dipropyl-1H-imidazo[4,5-b]pyridine-1-acetamidehydrate [1:0.5].

Under nitrogen bubbling, a mixture of2-(4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-1-acetic acid (3.83 g,0.013 mole) and 1,1'-carbonyldiimidazole (2.11 g, 0.013 mole) in 150 mlof tetrahydrofuran was stirred at room temperature for 4 hrs.Dipropylamine (2.63 g, 0.026 mole) was added and the reaction mixturewas heated at reflux for 2 hrs, followed by standing at room temperatureover the weekend. The tetrahydrofuran was evaporated to dryness andplaced under high vacuum overnight. The residue was dissolved inisopropyl alcohol, filtered, and diluted with water to produce acrystalline product upon refrigeration. The solid was collected byfiltration, washed with water, and dried under high vacuum overnight togive 1.22 g. A recrystallization from isopropyl alcohol-water gave 0.91g of title compound after drying under high vacuum at 50° C. over theweekend, mp 139°-141° C.

Analysis: Calculated for C₂₀ H₂₃ N₄ OCl.1/2H₂ O: C, 63.23; H, 6.37; N,14.75. Found: C, 62.92; H, 6.53; N, 14.54.

EXAMPLE 187 2-(4-Chlorophenyl)-1H-imidazo[4,5-b]pyridine-1-acetic acidethyl ester hydrochloride [1:1]

Under a nitrogen flow, sodium hydride (1.76 g, 0.044 mole, 60% in oil)was with hexanes (˜75 ml) and decanted. Dimethylformamide (150 ml) wasadded and the 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine (9.16 g,0.04 mole) was added in portions. The reaction mixture was heated at70°-85° C. for 11/2 hours. Ethyl bromoacetate (6.68 g, 0.04 mole) wasadded dropwise and the reaction mixture was allowed to stir at roomtemperature over the weekend. The reaction mixture was poured into waterand the precipitate was collected by filtration, washed with water, anddried under high vacuum at 50° C. overnight (78.6% crude yield). A 1.5-gsample was dissolved in ethyl acetate, acidified with ethereal hydrogenchloride, and the crystalline precipitate was collected by filtration,washed with ethyl acetate, and dried under high vacuum to give 1.55 g.The sample was recrystallized from acetonitrile to give 1.16 g afterdrying under high vacuum at 75° C. over the weekend, mp 199°-200° C.with decomposition.

Analysis: Calculated for C₂₆ H₁₄ N₃ O₂ Cl.HCl: C, 54.56; H, 4.29; N,11.93. Found: C, 54.29; H, 4.25; N, 12.05.

EXAMPLE 188 2-(4-Chlorophenyl)-1H-imidazo[4,5-b]pyridine-1-acetamide

Under nitrogen flow, sodium hydride (0.96 g, 0.0234 mole, 60% in oil)was washed with hexanes (˜70 ml) and decanted. Dimethylformamide wasadded (100 ml) and the 2-(4-chlorophenyl)-3-H-imidazo[4,5-b]pyridine(5.0 g, 0.022 mole) was added in portions. The reaction mixture washeated at 70°-85° C. for 11/2 hours. Chloroacetamide (2.06 g, 0.022mole) was added and the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was added to water (˜600 ml) and theprecipitate was collected by filtration, washed with water, and driedunder high vacuum overnight at 50° C. NMR indicated a 14% yield of theisomer: 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide and an86% yield of the title compound. The solid was dissolved in pyridine,filtered, and diluted with water to produce crystalline product withrefrigeration. The solid was collected by filtration, washed with waterand dried under high vacuum at 90° C. overnight to give 2.3 g (36.5%) ofthe title compound, mp 280°-283° C. with decomposition.

Analysis: Calculated for C₁₄ H₁₁ N₄ OCl: C, 58.65; H, 3.87; N, 19.54.Found: C, 58.38; H, 3.88; N, 19.26.

EXAMPLE 1892-(4-Bromophenyl)-N,N-dipropyl-3-H-imidazo[4,5-b]pyridine-3-acetamide

Under nitrogen bubbling, a mixture of2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (13.28 g, 0.04mole) and 1,1' carbonyldiimidazole (7.14 g, 0.044 mole) in 300 ml oftetrahydrofuran was stirred at room temperature for 6 hrs. Then, undernitrogen atmosphere, dipropylamine (12.12 g, 0.12 mole) was added andthe reaction mixture was heated at reflux for 3 hrs. The reactionmixture was filtered and the filtrate was evaporated to dryness. Thesolid was dried under high vacuum overnight and was recrystallized fromisopropyl alcohol-water. The crystalline solid was collected byfiltration, washed with water, and dried under high vacuum over theweekend to give 9.0 g (54%), mp 153°-55° C.

Analysis: Calculated for C₂₀ H₂₃ N₄ OBr: C, 57.84; H, 5.58; N, 13.49.Found: C, 57.65; H, 5.55; N, 13.43.

EXAMPLE 1902-(4-Chlorophenyl)-N-(4-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

Under a nitrogen atmosphere, oxalyl chloride (2.43 g, 0.01914 mole) wasadded dropwise, slowly, to a stirred and chilled solution of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) in dimethylformamide (60 ml). The reaction mixture was stirred atroom temperature for 1.5 hour. An additional portion of oxalyl chloride(0.5 ml, 0.0057 mole) was added. After additional stirring at roomtemperature for 0.5 hr, a solution of 4-aminopyridine (1.81 g, 0.0192mole) in dimethylformamide (10 ml) was added and the mixture was stirredat room temperature overnight. The mixture was poured into ice water(400 ml) and the resulting solid was collected by filtration, dissolvedin hot isopropyl alcohol, filtered hot, and cooled to room temperatureat give a solid. The solid was collected by filtration, rinsed withwater, and dried under high vacuum to give 1.0 g of title compound,mp>250° C.

Analysis: Calculated for C₁₉ H₁₅ N₅ O₁.5 Cl: C, 61.21; H, 4.06; N,18.78. Found: C, 61.23; H, 4.04; N, 18.67.

EXAMPLE 191 2-(4-Nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

A suspension of crude2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (1.5 g,0.00503 mole) in absolute ethanol was acidified with 0.5 ml ofconcentrated sulfuric acid and refluxed under nitrogen for three days.The solution was evaporated to approximately one-third of its originalvolume (reduced pressure), and saturated sodium bicarbonate solution andethyl acetate were added. The layers were separated, the aqueous layerwas re-extracted with ethyl acetate and the combined organic layers werewashed twice with water, dried over sodium sulfate, filtered, andevaporated under reduced pressure to give a solid. The solid wasdissolved in hot absolute ethanol and filtered hot. Upon cooling to roomtemperature, a solid formed which was collected by filtration, rinsedwith water, and dried under high vacuum at 50° C. overnight to give 1.17g (71%) of title compound, mp 191.5°-193.5° C.

Analysis: Calculated for C₁₆ H₁₄ N₄ O₄ : C, 58.89; H, 4.32; N, 17.17.Found: C, 58.85; H, 4.28; N, 17.13.

EXAMPLE 192(S)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

A suspension of crude(S)-2-(4-chlorophenyl)-αmethyl-3H-imidazo[4,5-b]pyridine-3-acetic acid(2.0 g, 0.00663 mole) in absolute ethanol was stirred at roomtemperature while 4 drops of concentrated sulfuric acid was added. Thereaction mixture was refluxed for three days. Approximately 1/2 to 2/3of the solvent was removed under reduced pressure. Saturated sodiumbicarbonate solution (20 ml) was added to the remaining solution. Theproduct was extracted into two portions of ethyl acetate and thecombined organic layers were washed twice with water, dried over sodiumsulfate, filtered and evaporated to an oil which was dissolved in hotabsolute ethanol. Water was added to the cloud point and upon cooling toroom temperature, a solid precipitated. The solid was collected byfiltration, rinsed with water and dried under high vacuum at 50° C. togive 1.48 g (68%) of title compound, mp 103°-106° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₂ Cl: C, 61.92: H, 4.89; N, 12.74.Found: C, 61.89; H, 4.86; N, 12.77.

EXAMPLE 1933-[2-(4-Acetyl-1-piperazinyl)-2-oxoethyl]-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (4.0 g, 0.014 mole), 1,1'-carbonyldiimidazole (2.26 g, 0.014 mole)and dry tetrahydrofuran (80 ml) was stirred at room temperature for 3 hrwith a stream of nitrogen bubbling through it. A solution of1-acetylpiperazine (4.49 g, 0.035 mole) in tetrahydrofuran (10 ml) wasadded and the resulting suspension was heated at 60° C. overnight. Thesolvent was evaporated under reduced pressure and the residue wastriturated in water (100 ml), filtered, and the filter cake rinsed withwater. The solid was dissolved in hot isopropyl alcohol, filtered hot,and allowed to cool to room temperature. The resulting solid wascollected by filtration and dried under high vacuum at 50° C. to yield3.18 g (57%) of title compound, mp 217°-219° C.

Analysis: Calculated for C₂₀ H₂₀ N₅ O₂ Cl: C, 60.38; H, 5.07; N, 17.60.Found: C, 60.40; H, 5.06; N, 17.60.

EXAMPLE 1942-(4-Chlorophenyl)-N-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldimidazole (2.82 g, 0.0174 mole)and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3hr with a stream for nitrogen bubbling through it. A solution of2-(2-aminoethyl)-1-methylpyrrole (5.40 g, 0.0435 mole) intetrahydrofuran (6 ml) was added and the mixture was stirred at roomtemperature under nitrogen overnight. The solvent was evaporated underreduced pressure and the resulting oil was triturated in water (100 ml)which caused a solid to form. The solid was collected by filtration,rinsed twice with water, twice with 5% potassium hydroxide solution andtwice again with water. The solid was dissolved in hot isopropyl alcoholand filtered hot. Water was added to the cloud point. Upon cooling, asolid precipitated which was collected by filtration, rinsed with water,and dried under high vacuum at 50° C. overnight to give 4.31 g (63%) oftitle compound, mp 171°-172.5° C.

Analysis: Calculated for C₂₁ H₂₀ N₅ OCl: C, 64.04; H, 5.12; N, 17.78.Found: C, 63.97; H, 5.09; N, 17.75.

EXAMPLE 1952-(4-Chlorophenyl)-N-[3-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate[1:1]

Under a nitrogen atmosphere, oxalyl chloride (2.03 g, 0.016 mole) wasadded dropwise, slowly, to a stirred and chilled solution of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014mole) in dry dimethylformamide (60 ml). The reaction mixture was stirredat room temperature for 1.5 hr, and then an additional 0.3 ml of oxalylchloride was added. After stirring for an additional 0.5 hr, thesolution was added dropwise to a stirred mixture ofN,N-dimethyl-1,3-benzenediamine dihydrochloride (3.35 g, 0.016 mole) andtriethylamine (6.46 g, 0.064 mole) in dimethylformamide (130 ml). Theresultant mixture was stirred at room temperature overnight and pouredinto 400 ml of ice water. The solid which precipitated was collected byfiltration, dissolved in hot isopropyl alcohol, and filtered hot. Uponcooling to room temperature, solid precipitated. Water was added and thesolid was collected by filtration and rinsed with water. A 0.5-g samplewas dried under high vacuum at room temperature to give 0.34 g of titlecompound, mp 215°-217° C.

Analysis: Calculated for C₂₂ H₂₂ N₅ O₂ Cl: C, 62.34; H, 5.23; N, 16.52.Found: C, 62.31; H, 5.19; N, 16.53.

EXAMPLE 1962-(4-Chlorophenyl)-N-[3-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate [1:2:0.5]

A solution of 2-(4-chlorophenyl)-N-[3-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide in hot isopropyl alcoholwas acidified with hydrogen chloride/isopropyl alcohol. Isopropyl etherwas added to the cloud point. Upon cooling to room temperature, solidformed which was collected by filtration, rinsed with isopropyl ether,and dried under high vacuum at 50° C. overnight to give 1.9 g of titlecompound, mp 166°-170° C. (shrinks), 183°-187° C. (melts).

Analysis: Calculated for C₂₂ H₂₃ N₅ O₁.5 Cl₃ : C, 54.17; H, 4.75; N,14.36. Found: C, 54.29; H, 4.72; N, 14.42.

EXAMPLE 1972-(4-Nitrophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of crude2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101mole), 1,1'-carbonyldi imidazole (1.63 g, 0.0101 mole) and drytetrahydrofuran (100 ml) was stirred at room temperature for three hourswith nitrogen bubbling through it and then refluxed under nitrogenovernight. The mixture was cooled to room temperature and a solution ofdipropylamine (3.06 g, 0.0302 mole) in tetrahydrofuran (5 ml) was added.The suspension was refluxed over the weekend under nitrogen. Thesolvents were removed under reduced pressure and the solid residue wastriturated in water (100 ml) overnight. The solid was collected byfiltration, rinsed twice with water, twice with 5% potassium hydroxidesolution and then twice more with water. The solid was dissolved in hotisopropyl alcohol, filtered while hot, and cooled to room temperature toprecipitate a solid. Water was added and the solid was collected byfiltration, rinsed with water and dried under high vacuum at 70° C. togive 1.23 g (32%) of title compound, mp. 205°-208° C.

Analysis: Calculated for C₂₀ H₂₃ N₅ O₃ : C, 62.98; H, 6.08; N, 18.36.Found: C, 62.63; H, 6.02; N, 18.34.

EXAMPLE 198N-Methyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of crude2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.0101mole), 1,1'-carbonyldiimidazole (1.63 g, 0.0101 mole) and drytetrahydrofuran (100 ml) was stirred at room temperature for three hourswith a stream of nitrogen bubbling through it and then refluxedovernight under nitrogen. It was cooled to room temperature and asolution of methylamine (0.94 g, 0.0302 mole) in tetrahydrofuran (10 ml)was added and the reaction mixture was stirred at room temperature overthe weekend. The solvents were removed under reduced pressure and theresulting solid was triturated in water, collected by filtration, rinsedonce with water, once with 5% potassium hydroxide solution and once withwater. The solid was dissolved in hot isopropyl alcohol, filtered hotcooled in the refrigerator to precipitate a solid. Water was added andthe solid was collected by filtration and dried under high vacuum at 70°C. to give 0.42 g (13%) of title compound, mp.>260° C.

Analysis: Calculated for C₁₅ H₁₃ N₅ O₃ : C, 57.88; H, 4.21; N, 22.50.Found: C, 57.66; H, 4.23; N, 22.30.

EXAMPLE 1992-(5-Bromo-2-furanyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

A suspension of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0155 mole), and 1,1'-carbonyldiimidazole (2.52 g, 0.0155mole) in dry tetrahydrofuran (100 ml) was stirred at room temperaturefor two hours with a stream of nitrogen bubbling through it. A solutionof dimethylamine in tetrahydrofuran (40.6 ml of a 2.29M solution, 0.093mole) was added, and the resulting solution was heated at 45° C.overnight under a nitrogen atmosphere. The reaction mixture wasevaporated to a solid which was triturated in water (100 ml), collectedby filtration, and rinsed twice with water, twice with a 5% potassiumhydroxide solution, and twice again with water. The solid was dissolvedin hot isopropyl alcohol, filtered, and allowed to cool to roomtemperature. Addition of water caused a precipitate to form which wascollected by filtration, rinsed with water, and dried at high vacuum togive 3.16 g (58%) of title compound, mp 182°-185° C.

Analysis: Calculated for C₁₄ H₁₄ N₄ O₂.5 Br: C, 46.94; H, 3.94; N,15.64. Found: C, 46.91; H, 4.12; N, 15.63.

EXAMPLE 2002-(5-Bromo-2-furanyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine aceticacid (5.0 g, 0.0155 mole) and 1,1'-carbonyldiimidazole (2.52 g, 0.0155mole) in dry tetrahydrofuran (100 ml) was stirred at room temperaturefor two hours with a stream of nitrogen bubbling through it. A solutionof methylamine in tetrahydrofuran (31 ml of a 3.03M solution, 0.093mole) was added, and the suspension was stirred at room temperatureovernight under a nitrogen atmosphere. The reaction mixture wasevaporated under reduced pressure, and the residue was triturated inwater. The resulting solid was collected by filtration and rinsed twicewith water, twice with a 5% potassium hydroxide solution, and twiceagain with water. The solid was dissolved in hot isopropyl alcohol andfiltered, and the solution was allowed to cool to room temperature.Addition of water caused a precipitate to form which was collected byfiltration and dried under high vacuum to give 2.95 g (57%) of titlecompound, mp. 187°-191° C.

Analysis: Calculated for C₁₃ H₁₁ N₄ O₂ Br: C, 46.59; H, 3.31; N, 16.72.Found: C, 46.05; H, 3.59; N, 16.44.

EXAMPLE 201N,N-Dimethyl-2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (3.0 g, 0.0101 mole), 1,1'-carbonyldiimidazole (1.6 g, 0.0101mole), and dry dimethylformamide (10 ml) in tetrahydrofuran (100 ml) wasstirred at room temperature for two hours with nitrogen bubbling throughit. A solution of dimethylamine in tetrahydrofuran (26.4 ml of a 2.29Msolution, 0.0606 mole) was added. The resulting solution was heated at45° C. overnight under nitrogen. The solvents were evaporated underreduced pressure. The residue was triturated in water (300 ml), and theresulting solid was collected by filtration, rinsed with water, 5%potassium hydroxide solution and again with water. The solid wasdissolved in hot isopropyl alcohol, filtered, and allowed to cool toroom temperature. A solid precipitated which was collected by filtrationand dried under high vacuum to give 1.26 g (38%) of title compound, mp204°-207° C.

Analysis: Calculated for C₁₆ H₁₅ N₅ O₃ : C, 59.07; H, 4.65; N, 21.53.Found: C, 58.86; H, 4.85; N, 21.54.

EXAMPLE 2022-(4-Chlorophenyl)-N-methyl-N-propyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:2]

A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor 2.5 hours with a stream of nitrogen bubbling through it. A solutionof methylpropylamine (3.81 g, 0.0522 mole) in tetrahydrofuran (4 ml) wasadded, and the reaction mixture was heated at 45° C. for 15 hours, thenstirred at room temperature. The solvents were evaporated under reducedpressure, and the resulting oil was triturated in water (100 ml) whichcaused a solid to form. The solid was collected by filtration and washedwith water, twice with a 5% potassium hydroxide solution, and twiceagain with water. The solid was dissolved in hot isopropyl alcohol,filtered, and cooled to room temperature. Addition of water to the cloudpoint caused crystals to form. The solid was collected by filtration,rinsed with water, and dried at high vacuum to give 3.60 g (60%) oftitle compound, mp 130°-133° C.

Analysis: Calculated for C₁₈ H₂₃ N₄ O₃ Cl: C, 57.06; H, 6.12; N, 14.79.Found: C, 57.27; H, 5.95; N, 14.80.

EXAMPLE 2032-(5-Bromo-2-furanyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine aceticacid (5.0 g, 0.0155 mole), 1,1'-carbonyldiimidazole (2.52 g, 0.0155mole) and dry tetrahydrofuran (100 ml) was stirred at room temperaturefor 2.5 hours with a stream of nitrogen bubbling through it. A solutionof dipropylamine 4.71 g, 0.046 mole) in tetrahydrofuran (6 ml) was addedand the reaction mixture was refluxed for 15 hours, then stirred at roomtemperature. The solvents were removed under reduced pressure, and theresulting oil was partitioned between ethyl acetate (100 ml) and water(100 ml). The layers were separated, and the aqueous layer wasre-extracted with ethyl acetate. The combined organic layers were washedwith water, twice with a 5% potassium hydroxide solution and twice againwith water, dried with magnesium sulfate, charcoaled, and filtered. Thesolvent was removed under reduced pressure to give an oil whichcrystallized upon trituration with isopropyl ether. The solid wascollected by filtration and dried under high vacuum to give 2.0 g (32%)of title compound, mp 102°-104° C.

Analysis: Calculated for C₁₈ H₂₁ N₄ O₂ Br: C, 53.34; H, 5.22; N, 13.82.Found: C, 53.63; H, 5.25; N, 13.48.

EXAMPLE 204(R)-2-(4-Chlorophenyl)-N,α-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole),1,1'carbonyldiimidazole (2.69 g, 0.0166 mole), and dry tetrahydrofuran(100 ml) was stirred at room temperature for 1.75 hours with a stream ofnitrogen bubbling through it. A solution of methylamine intetrahydrofuran (33 ml of a 3.03M solution, 0.996 mole) was added andthe reaction mixture was stirred at room temperature overnight undernitrogen. The solvents were removed under reduced pressure and theresulting solid was triturated in water, collected by filtration, rinsedtwice with water, twice with 5% potassium hydroxide solution, and twiceagain with water. The solid was dissolved in hot isopropyl alcohol,charcoaled, and filtered while hot. Water was added to the cloud point,and upon cooling, solid precipitated. The solid was collected byfiltration and dried under high vacuum at 50° C. overnight to give 3.21g (62%) of title compound, mp 217°-218° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ O₁ Cl: C, 61.05; H, 4.80; N, 17.80.Found: C, 60.84; H, 4.95; N, 17.64.

EXAMPLE 205(S)-2-(4-Chlorophenyl)-N,α-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole),1,1'-carbonyldiimidazole (1.61 g, 0.00995 mole) and dry tetrahydrofuran(60 ml) was stirred at room temperature for 1.75 hours with a stream ofnitrogen bubbling through it. A solution of methylamine intetrahydrofuran (20 ml of a 3.03M solution, 0.060 mole) was added andthe reaction mixture was stirred at room temperature overnight undernitrogen. The solvents were removed under reduced pressure and theresulting solid was triturated in water, collected by filtration, rinsedtwice with water, twice with 5% potassium hydroxide solution, and twiceagain with water. The solid was dissolved in hot isopropyl alcohol andfiltered hot. Upon cooling to room temperature, solid precipitated whichwas collected by filtration and dried under high vacuum at 50° C.overnight to give 0.86 g (28%) of title compound, mp 218°-220° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OCl: C, 61.05; H, 4.80; N, 17.80.Found: C, 60.97; H, 4.96; N, 17.89.

EXAMPLE 206(S)-2-(4-Chlorophenyl)-N-[4-(dimethylamino)phenyl]-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrochloride hydrate[1:2:1]

Under a nitrogen atmosphere, oxalyl chloride (2.41 g, 0.019 mole) wasadded dropwise, slowly, to a stirred and chilled (10° C.) suspension of(S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo [4,5-b]pyridine-3-acetic acid(5.0 g, 0.0166 mole) in anhydrous dimethylformamide (75 ml). Thesuspension was stirred at room temperature for 30 minutes and then anadditional portion of oxalyl chloride (0.73 g, 0.0057 mole) was added.The resulting solution was stirred at room temperature for 45 minutesand then added slowly to a suspension of N,N-dimethyl-1,4-benzenediaminedihydrochloride (3.97 g, 0.0019 mole) and triethylamine (7.7 g, 0.076mole) in anhydrous dimethylformamide (150 ml). The reaction mixture wasstirred at room temperature overnight under nitrogen and protected fromlight. The solution was then poured into 400 ml of ice water. Theresulting solid was collected by filtration, rinsed with water,dissolved in hot isopropyl alcohol, filtered, and cooled to roomtemperature. Upon addition of water, solid precipitated. The solid wascollected by filtration, dissolved in hot tetrahydrofuran, and madeacidic with ethereal hydrogen chloride. The solid was collected byfiltration, rinsed with isopropyl ether, and dried under high vacuum at50° C. to give 4.0 g (47%) of title compound, mp 186°-190° C.

Analysis: Calculated for C₂₃ H₂₆ N₅ O₂ Cl₃ : C, 54.08; H, 5.13; N,13.71. Found: C, 54.49; H, 4.95; N, 13.39.

EXAMPLE 207(R)-2-(4-Chlorophenyl)-N,N,α-trimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole),1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran(100 ml) was stirred at room temperature for 2.25 hours with a stream ofnitrogen bubbling through it. A solution of dimethylamine intetrahydrofuran (22 ml of a 2.29M solution, 0.050 mole) was added andthe reaction mixture was heated at 45° C. for two days under nitrogen.The solvents were removed under reduced pressure and the residue waspartitioned between water and ethyl acetate. The ethyl acetate layer waswashed twice with water, twice with a 5% potassium hydroxide solutionand twice again with water. It was then dried over magnesium sulfate,charcoaled, filtered, and evaporated to a residue which was dissolved inhot isopropyl ether, filtered, and cooled to room temperature. Theresulting solid was collected by filtration and dried under high vacuumat 50° C. to give 2.61 g (48%) of title compound, mp 124°-127° C.

Analysis: Calculated for C₁₇ H₁₇ N₄ OCl: C, 62.10; H, 5.21; N, 17.04.Found: C, 62.18; H, 5.09; N, 17.10.

EXAMPLE 208(R)-2-(4-Chlorophenyl)-α-methyl-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole).1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran(100 ml) was stirred at room temperature for 2.25 hours with nitrogenbubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) intetrahydrofuran (7 ml) was added and the reaction mixture was refluxedunder nitrogen for two days. The solvents were removed under reducedpressure and the residue was partitioned between water and ethylacetate. The ethyl acetate layer was washed twice with water, twice witha 5% potassium hydroxide solution, and twice again with water. It wasthen dried over magnesium sulfate, charcoaled, filtered, and evaporatedto an oil which crystallized upon trituration with isopropyl ether. Thesolid was collected by filtration and dried under high vacuum at 50° C.overnight to give 1.96 g (31%) of title compound, mp 95°-97° C.

Analysis: Calculated for C₂₁ H₂₅ N₄ OCl: C, 65.53; H, 6.55; N, 14.56.Found: C, 65.52; N, 6.51; N, 14.54.

EXAMPLE 2091-[2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-yl]propanone

The free base of 2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-ethanol (6.3 g, 0.019 mole) was prepared bypartitioning its hydrochloride salt between methylene chloride anddilute aqueous base. The methylene chloride layer was separated and theaqueous basic layer was extracted with methylene chloride (2×). Themethylene chloride layers were combined, extracted with saturated sodiumchloride, and dried over anhydrous sodium sulfate. The methylenechloride filtrate was evaporated and dried under high vacuum overnight.

Under nitrogen atmosphere, the free base from above in 25 ml ofmethylene chloride was added in one portion to a magnetically stirredsuspension of pyridinium chlorochromate (6.28 g, 0.029 mole) in 50 ml ofmethylene chloride. After two hours, a 50-ml portion of diethyl etherwas added to the reaction mixture and the supernatant liquid wasdecanted from a black gum. The insoluble residue was triturated withboiling methylene chloride (3×). The combined organic solvents weretreated with Florisil®, filtered, and evaporated to a solid (4.4 g). NMRindicated 50% starting material/50% product.

Under nitrogen atmosphere, the 4.4 g of solid in 25 ml of methylenechloride was added to a magnetically stirred suspension of pyridiniumchlorochromate (5.0 g, 0.023 mole) in50 ml of methylene chloride.Allowed to stir at ambient temperature overnight. The reaction solventwas decanted and the residue was triturated with hot methylene chloride(3×). The combined organic solvents were treated with Florisil®,filtered, and evaporated to a solid. NMR indicated complete oxidation toketone. The solid was recrystallized from isopropyl alcohol withrefrigeration. The product was collected by filtration, washed withwater, and dried under high vacuum first at room temperature overnight,then at 50° C. for 1/2 day to give crystalline solid, 2.2 g (40%), mp172°-173.5° C.

Analysis: Calculated for C₁₅ H₁₂ N₃ OCl: C, 63.05; H, 4.23; N, 14.71.Found: C, 62.89; H, 4.15; N, 14.63.

EXAMPLE 210(R)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid2-hydroxyethyl ester hydrochloride [1:1]

A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alaninemethyl ester (42.5 g, 0.0127 mole) in ethylene glycol (250 ml) wasrefluxed under nitrogen for one hour. The solution was cooled to roomtemperature and approximately 5 ml of the solution was added to water.Ethyl acetate was added and the layers were separated. The aqueous layerwas extracted with two additional portions of ethyl acetate and thecombined organic layers were washed three times with a saturated sodiumchloride solution. The ethyl acetate layer was dried over sodiumsulfate, filtered, and evaporated to an oil under reduced pressure. Theoil was dissolved in isopropyl alcohol and was made acidic with hydrogenchloride/isopropyl alcohol. Addition of isopropyl ether to the cloudpoint gave a solid. The solid was collected by filtration, rinsed withisopropyl ether and dried under high vacuum at room temperature to give0.25 g of title compound, mp 191°-195° C.

Analysis: Calculated for C₁₇ H₁₇ N₃ O₃ Cl₂ : C, 53.42; H, 4.48; N,10.99. Found: C, 53.24; H, 4.50; N, 10.78.

EXAMPLE 2112-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-ethanolhydrochloride [1:1]

The solid 4-chloro-N-[2-[(2-hydroxypropyl)amino]-3-pyridinyl]benzamidemonohydrochloride (12.3 g, 0.04 mole) was heated in a glass beaker at180°-185° C. with a Wood's metal bath under nitrogen flow for twelveminutes. The residue was dissolved in tetrahydrofuran, filtered, and thefiltrate was acidified with ethereal hydrogen chloride. The crystallinesolid was collected by filtration, washed with tetrahydrofuran and driedunder high vacuum overnight. A portion of the solid was recrystallizedfrom methanol and diethyl ether and dried under high vacuum at 50° C.overnight to give 1.6 g (total crude yield 8.55 g, 66%), mp 206°-211° C.

Analysis: Calculated for C₁₅ H₁₄ N₃ OCl.HCl: C, 55.57; H, 4.66; N,12.96. Found: C, 55.44; H, 4.79; N, 13.10.

EXAMPLE 212 2-(5-Methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid

A suspension ofN-[3-[(5-methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester(93.8 g, 0.293 mole) was refluxed in ethylene glycol (500 ml) for 45minutes. The solution was cooled and water (200 ml) and solid potassiumhydroxide pellets (23.25 g, 0.41 mole) were added. The resultingsolution was refluxed for one hour and then filtered hot into ice water(2 liters) and acidified with 3N hydrochloric acid to give a solid whichwas collected by filtration and dried to give 52.3 g of crude titlecompound (65% yield). A 2.0-g portion was dissolved in hot methanol,treated with charcoal, filtered while hot, and cooled to roomtemperature. Addition of water caused a precipitate to form which wascollected by filtration and dried under high vacuum at room temperatureovernight to give 0.68 g of title compound, mp>250° C.

Analysis: Calculated for C₁₃ H₁₁ N₃ O₂ S: C, 57.13; H, 4.00; N, 15.37.Found: C, 57.12; H, 3.99; N, 15.24.

EXAMPLE 213A(S)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid2-hydroxyethyl ester

A solution of crude(S)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alanine ethyl ester (37 g,0.11 mole) was refluxed in ethylene glycol (200 ml) for 1.5 hours andcooled. Approximately 1/3 of the volume was removed, added to water (800ml) and extracted twice into ethyl acetate. The combined organic layerwas washed three times with water, dried over magnesium sulfate, treatedwith charcoal, filtered and evaporated under reduced pressure to an oilwhich crystallized upon standing. It was triturated in isopropyl alcoholand filtered, and the mother liquor was evaporated to give 8.0 g of aresidue (66% yield). The residue was dissolved in hot isopropyl ether,treated with charcoal, filtered while hot and cooled to roomtemperature. A solid precipitated which was collected by filtration andrecrystallized from hot isopropyl ether to give 2.03 g of titlecompound, mp 114°-118° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₃ Cl: C, 59.05; H, 4.66; N, 12.15.Found: C, 58.79; H, 4.60; N, 12.06.

EXAMPLE 213B(S)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid2-hydroxyethyl ester

A solution of(S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid(3.0 g, 0.00995 mole) and concentrated sulfuric acid (4 drops) inethylene glycol (50 ml) was refluxed under nitrogen for three hours, andthen poured into a saturated sodium bicarbonate solution (200 ml). Water(50 ml) was added and the product was extracted into two portions ofethyl acetate. The combined organic layers were washed twice with waterand once with a saturated sodium chloride solution, dried over magnesiumsulfate, treated with charcoal and filtered. Evaporation of the solventsunder reduced pressure gave 1.9 g (56% yield) of solid which wasdissolved in hot isopropyl ether (with a little isopropyl alcoholadded). The solution was stirred and cooled to room temperature toprecipitate a solid. The mixture was cooled in the freezer, the solidwas collected by filtration, rinsed with isopropyl ether and dried underhigh vacuum at room temperature overnight to give 1.44 g of titlecompound, mp 112°-113.5° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₃ Cl: C, 59.05; H, 4.66; N, 12.15.Found: C, 58.98; H, 4.65; N, 12.11.

EXAMPLE 214N,N-Dimethyl-2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183mole) in tetrahydrofuran (100 ml) was stirred at room temperature for33/4 with a stream of nitrogen bubbling through it. A solution ofdimethylamine (48 ml of a 2.29M solution in tetrahydrofuran, 0.1098mole) was added and the mixture was heated at 40° C. overnight undernitrogen. The solvents were removed under reduced pressure and theresidue was partitioned between water and ethyl acetate. The layers wereseparated and the aqueous layer was extracted again with ethyl acetate.The combined organic layer was washed twice with a saturated sodiumchloride solution, twice with a 5% potassium hydroxide solution andtwice again with a saturated sodium chloride solution. The organic layerwas dried over magnesium sulfate, treated with charcoal, filtered andevaporated under reduced pressure to give a residue which was dissolvedin hot isopropyl alcohol and brought to the cloud point by addition ofisopropyl ether. Upon cooling to room temperature, a solid precipitatedwhich was collected by filtration, rinsed with isopropyl ether, anddried under high vacuum at room temperature to give 1.13 g of titlecompound (20%), mp 193°-197° C.

Analysis: Calculated for C₁₅ H₁₆ N₄ OS: C, 59.98; N, 5.37; N, 18.65.Found: C, 59.66; H, 5.32; N, 18.46.

EXAMPLE 215N-Methyl-2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183mole) in tetrahydrofuran (100 ml) was stirred at room temperature for33/4 hours with a stream of nitrogen bubbling through it. A solution ofmethylamine (36 ml of a 3.03M solution in tetrahydrofuran, 0.1098 mole)was added and the reaction mixture was stirred at room temperatureovernight under nitrogen. The solvents were removed under reducedpressure and the resulting solid was triturated in water (100 ml),collected by filtration, and rinsed twice with water, twice with a 5%potassium hydroxide solution, and twice again with water. The solid wasdissolved in hot isopropyl alcohol, and filtered while hot. Addition ofisopropyl ether caused solid to precipitate. The solid was collected byfiltration, rinsed with isopropyl ether, and dried under high vacuum atroom temperature overnight to give 3.12 g (60%) of title compound, mp213°-216° C.

Analysis: Calculated for C₁₄ H₁₄ N₄ OS: C, 58.72; H, 4.93; N, 19.56.Found: C, 58.56; H, 4.93; N, 19.43.

EXAMPLE 216 2-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid2-hydroxyethyl ester

A solution of N-[3-[(4-fluorobenzoyl)amino]-2-pyridinyl]glycine ethylester (70.0 g, 0.2205 mole) in ethylene glycol was refluxed for 2 hours,cooled, and 14% for the solution (0.030 mole) was removed. Water (550ml) was added to this aliquot, causing a solid to precipitate. Theproduct was extracted into ethyl acetate twice and the combined organiclayers were washed once with water and three times with a saturatedsodium chloride solution, dried over magnesium sulfate, treated withcharcoal, filtered, and evaporated to give 7.0 g of a white solidconsisting of a mixture of title compound and2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester.This was dissolved in methylene chloride and purified using a silica gelcolumn (100 g) and 1:1 methylene chloride/ethyl acetate and also 15%absolute ethanol in ethyl acetate as eluting solvents. The fractioncontaining pure title compound was evaporated under reduced pressure togive 1.98 g (21%) of title compound, mp 166.5°-168.5° C.

Analysis: Calculated for C₁₆ H₁₄ N₃ O₃ F: C, 60.95; H, 4.48; N, 13.33.Found: C, 60.99; H, 4.48; N, 13.31.

EXAMPLE 217 2-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester

A solution N-[3-[(4-fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester(70.0 g, 0.02205 mole) in ethylene glycol was refluxed for 2 hours,cooled, and 14% of the solution (0.30 mole) was removed. Water (550 ml)was added to this aliquot, causing a solid to precipitate. The productwas extracted into ethyl acetate twice and the combined organic layerswere washed once with water and three times with a saturated sodiumchloride solution, dried over magnesium sulfate, treated with charcoal,filtered, and evaporated to give 7.0 g of a white solid consisting of amixture of title compound and2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3acetic acid 2-hydroxyethylester. This was dissolved in methylene chloride and purified using asilica gel (100 g) column and 1:1 methylene chloride/ethyl acetate andalso 15% absolute ethanol in ethyl acetate as eluting solvents. Thefraction containing pure title compound was evaporated under reducedpressure to give 1.72 g (19%) of title compound, mp 126°- 128° C.

Analysis: Calculated for C₁₆ H₁₄ N₃ O₂ F: C, 64.21; H, 4.71; N, 14.04.Found: C, 64.23; H, 4.67; N, 14.04.

EXAMPLE 218(R)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid

A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alaninemethyl ester (42.5 g, 0.127 mole) in ethylene glycol (250 ml) wasrefluxed under nitrogen atmosphere for one hour and then cooled. Water(40 ml) and solid potassium hydroxide pellets (10.13 g, 0.181 mole) wereadded and the solution was refluxed for an additional two hours,filtered into ice water (1 liter) and acidified with 3N hydrochloricacid solution to give a solid which was collected by filtration andrinsed with water to give 29 g of crude title compound (76%) yield). A3.5-g portion of the solid was recrystallized twice from isopropylalcohol/water and dried under high vacuum at 50° C. overnight to give1.81 g of title compound, mp 225°-227° C.

Analysis: Calculated for C₁₅ H₁₂ N₃ O₂ Cl: C, 59.71; H, 4.01; N, 13.93.Found: C, 59.51; H, 4.07; N, 13.68.

EXAMPLE 2192-(5-Methyl-2-thienyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 3hours with a stream of nitrogen bubbling through it. A solution ofdipropylamine (5.56 g, 0.055 mole) in tetrahydrofuran (7 ml) was addedand the reaction mixture was stirred overnight at room temperature. Thesolvents were evaporated and the residue was partitioned between waterand ethyl acetate. The layers were separated and the aqueous layer wasextracted again with ethyl acetate. The combined organic layer waswashed twice with water, twice with a 5% potassium hydroxide solution,and twice again with water. The organic layer was dried over magnesiumsulfate, treated with charcoal, filtered, and evaporated to give a solidwhich was dissolved in hot isopropyl alcohol and filtered while hot.Addition of water and cooling caused a solid to precipitate. The solidwas dissolved again in hot isopropyl alcohol with charcoal, filteredwhile hot and brought to the cloud point by addition of water. Uponcooling, solid precipitated which was collected by filtration, rinsedwith water, and dried under high vacuum at 50° C. overnight to give 2.28g (35%) of title compound, mp 125°-127° C.

Analysis: Calculated for C₁₉ H₂₄ N₄ OS: C, 64.02; H, 6.78; N, 15.72.Found: C, 63.90; H, 6.79; N, 15.69.

EXAMPLE 220 2-(5-Bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid ethyl ester

A solution ofN-[3-[(5-bromo-2-furanylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester(110 g, 0.30 mole) was refluxed in ethylene glycol (510 ml) for 2 hours.A 20-ml aliquot (0.01 mole) was removed and water was added to thesample. The product was extracted twice into ethyl acetate and thecombined organic layer was washed several times with water, dried overmagnesium sulfate, charcoaled, filtered, and evaporated under reducedpressure to give 2.5 g of crude title compound (73% yield). The solidwas dissolved in hot isopropyl alcohol, filtered while hot, brought tothe cloud point by addition of water and cooled to give a solid whichwas purified on a column of 20 g of silica gel using 1:1 methylenechloride/ethyl acetate as the eluting solvent. Evaporation of thesolvent from the pure fraction gave 1.2 g of product which wasrecrystallized from isopropyl alcohol/water and dried under high vacuumat room temperature overnight to give 0.88 g of title compound, mp122.5°-125° C.

Analysis: Calculated for C₁₄ H₁₂ N₃ O₃ Br: C, 48.02; H, 3.45; N, 12.00.Found: C, 47.83; H, 3.40; N, 11.93.

EXAMPLE 221 2-(5-Methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid ethyl ester

A solution ofN-[3-[(5-methyl-2-thienylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester(93.8 g, 0.293 mole) in ethylene glycol (500 ml) was refluxed for 45minutes and cooled. A 10-ml aliquot was taken (0.005 mole) and added towater. The product was extracted into ethyl acetate twice and thecombined organic layer was washed twice with water, dried over magnesiumsulfate, treated with charcoal, filtered, and evaporated under reducedpressure to give 0.8 g (53% yield) of solid. The solid wasrecrystallized from isopropyl alcohol/water to give 0.31 g of solidwhich was purified on a silica gel column using 1:1 methylenechloride/ethyl acetate as the eluting solvent. Evaporation of thesolvent from the pure fraction and recrystallization of the resultingsolid from isopropyl alcohol/water give title compound, mp 123°-125° C.

Analysis: Calculated for C₁₅ H₁₅ N₃ O₂ S: C, 59.78; H, 5.02; N, 13.94.Found: C, 59.61; H, 5.05; N, 13.67.

EXAMPLE 222 a to k

The following compounds are reacted with sodium hydride and the productthereof is reacted with N,N-dimethyl-chloroacetamide:

(a) 2-(4-chlorophenyl)-7-chloro-3H-imidazo[4,5-b]pyridine,

(b) 2-(4-chlorophenyl)-6-chloro-3H-imidazo[4,5-b]pyridine,

(c) 2-(4-chlorophenyl)-5,7-dichloro-3H-imidazo[4,5-b]pyridine,

(d) 2-(4-chlorophenyl)-6-nitro-3H-imidazo[4,5-b]pyridine,

(e) 2-(4-chlorophenyl)-5-methoxy-3H-imidazo[4,5-b]pyridine,

(f) 2-(4-chlorophenyl)-5,6-dichloro-3H-imidazo[4,5-b]pyridine,

(g) 2-(4-chlorophenyl)-6-bromo-3H-imidazo[4,5-b]pyridine,

(h) 2-(4-chlorophenyl)-5-chloro-3H-imidazo[4,5-b]pyridine,

(i) 2-(4-chlorophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine,

(j) 2-(4-chlorophenyl)-6-methyl-3H-imidazo[4,5-b]pyridine, and

(k) 2-(4-chlorophenyl)-5-methyl-3H-imidazo[4,5-b]pyridine

to give mixtures of the following pairs of compounds which are separatedby dissolving out the minor constituent with an appropriate solvent (seeExample 188):

(a)2-(4-chlorophenyl)-7-chloro-N,N-dimethyl-1H-imidazo[4,5-b]pyridine-1-acetamideand2-(4-chlorophenyl)-7-chloro-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(b)2-(4-chlorophenyl)-6-chloro-N,N-dimethyl-1H-imidazo[4,5-b]pyridine-1-acetamideand2-(4-chlorophenyl)-6-chloro-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(c) 2-(4-chlorophenyl)-5,7-dichloro-N,N-dimethyl-1H-imidazo[4,5-b]pyridine-1-acetamide and2-(4-chlorophenyl)-5,7-dichloro-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(d)2-(4-chlorophenyl)-N,N-dimethyl-6-nitro-1H-imidazo[4,5-b]pyridine-1-acetamideand2-(4-chlorophenyl)-N,N-dimethyl-6-nitro-3H-imidazo[4,5-b]pyridine-3-acetamide,

(e)2-(4-chlorophenyl)-N,N-dimethyl-5-methoxy-1H-imidazo[4,5-b]pyridine-1-acetamideand2-(4-chlorophenyl)-N,N-dimethyl-5-methoxy-3H-imidazo[4,5-b]pyridine-3acetamide,

(f) 2-(4-chlorophenyl)-5,6-dichloro-N,N-dimethyl-1H-imidazo[4,5-b]pyridine-1-acetamide and2-(4-chlorophenyl)-5,6-dichloro-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(g)6-bromo-2-(4chlorophenyl)-N,N-dimethyl-1H-imidazo[4,5-b]pyridine-1-acetamideand6-bromo-2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(h)2-(4-chlorophenyl)-5-chloro-N,N-dimethyl-1H-imidazo[4,5-b]pyridine-1-acetamideand2-(4-chlorophenyl)-5-chloro-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(i)2-(4-chlorophenyl)-N,N-dimethyl-7-methyl-1H-imidazo[4,5-b]pyridine-1-acetamideand2-(4-chlorophenyl)-N,N-dimethyl-7-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(j)2-(4-chlorophenyl)-N,N-dimethyl-6-methyl-1H-imidazo[4,5-b]pyridine-1acetamideand2-(4-chlorophenyl)-N,N-dimethyl-6-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide,

(k)2-(4-chlorophenyl)-N,N-dimethyl-5-methyl-1H-imidazo[4,5-b]pyridine-1-acetamideand2-(4-chlorophenyl)-N,N-dimethyl-5-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide.

EXAMPLE 223 a to i

The following compounds are reacted with sodium hydride and the productthereof is reacted with chloroacetamide:

(a) 2-(4-chlorophenyl)-4methoxy-3H-imidazo[4,5-c]pyridine,

(b) 2-(4-chlorophenyl)-6-chloro-7-bromo-3H-imidazo[4,5-c]pyridine,

(c) 2-(4-chlorophenyl)-3H-imidazo[4,5-c]pyridine,

(d) 2-(4-chlorophenyl)-4-chloro-3H-imidazo[4,5-c]pyridine,

(e) 2-(4-chlorophenyl)-4,6-dichloro-3H-imidazo[4,5-c]pyridine,

(f) 2-(4-chlorophenyl)-7-nitro-3H-imidazo[4,5-c]pyridine,

(g) 2-(4-chlorophenyl)-4chloro-6-bromo-3H-imidazo[4,5-c]pyridine,

(h) 2-(4-chlorophenyl)-7-bromo-3H-imidazo[4,5-c]pyridine and

(i) 2-(4-chlorophenyl)-6chloro-1H-imidazo[4,5-c]pyridine

to give mixtures of the following pairs of compounds which are separateddissolving out the minor constituent with an appropriate solvent:

(a) 2-(4-chlorophenyl)-4-methoxy-1H-imidazo[4,5-c]pyridine-1-acetamideand 2-(4-chlorophenyl)-4-methoxy-3H-imidazo[4,5-c]pyridine-3-acetamide,

(b)7-bromo-2-(4-chlorophenyl)-6-chloro-1H-imidazo[4,5-c]pyridine-1-acetamideand7-bromo-2-(4-chlorophenyl)-6-chloro-3H-imidazo[4,5-c]pyridine-3-acetamide,

(c) 2-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridine-1-acetamide and2-(4-chlorophenyl)-3H-imidazo[4,5-c]pyridine-3-acetamide,

(d) 2-(4-chlorophenyl)-4-chloro-1H-imidazo[4,5-c]pyridine-1-acetamideand 2-(4-chlorophenyl)-4-chloro-3-imidazo[4,5-c]pyridine-3-acetamide,

(e)2-(4-chlorophenyl)-4,6-dichloro-1H-imidazo[4,5-c]pyridine-1-acetamideand2-(4-chlorophenyl)-4,6-dichloro-3H-imidazo[4,5-c]pyridine-3-acetamide,

(f) 2-(4-chlorophenyl)-7-nitro-1H-imidazo[4,5-c]pyridine-1-acetamide and2-(4-chlorophenyl)-7-nitro-3H-imidazo[4,5-c]pyridine-3acetamide,

(g)6-bromo-2-(4-chlorophenyl)-4-chloro-1H-imidazo[4,5-c]pyridine-1-acetamideand6-bromo-2-(4-chlorophenyl)-4-chloro-3H-imidazo[4,5-c]pyridine-3-acetamide,

(h) 7-bromo-2-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridine-1-acetamide and7-bromo-2-(4-chlorophenyl)-3H-imidazo[4,5-c]pyridine-3-acetamide,

(i) 2-(4-chlorophenyl)-6-chloro-1H-imidazo[4,5-c]pyridine-1-acetamideand 2-(4-chlorophenyl)-6-chloro-3H-imidazo[4,5-c]pyridine-3-acetamide.

EXAMPLE 224

Following the procedure of Example 25, but substituting the followingfor N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester:

(a) N-[3-(4-chlorobenzoylamino)-4-methyl-2-pyridinyl]glycine ethylester,

(b) N-[3-(4-chlorobenzoylamino)-5-methyl-2-pyridinyl]glycine ethylester,

(c) N-[3-(4-chlorobenzoylamino)-6-methyl-2-pyridinyl]glycine ethylester,

(d) N-[3-(4-chlorobenzoylamino)-5,6-dimethyl-2-pyridinyl]glycine ethylester,

(e)N-[5-(4-chlorobenzoylamino)-6-diethylamino-2-methyl-4-pyridinyl]glycineethyl ester,

(f) N-[3-(4-chlorobenzoylamino)-2-methyl-4-pyridinyl]glycine ethyl esterand

(g) N-[3-(4-chlorobenzoylamino)-6-methoxy-2-pyridinyl]glycine ethylester

there are obtained:

(a) 2-(4-chlorophenyl)-7-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester,

(b) 2-(4-chlorophenyl)-6-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester,

(c) 2-(4-chlorophenyl)-5-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester,

(d) 2-(4-chlorophenyl)-5,6-dimethyl-3H-imidazo[4,5-b]pyridine-3-aceticacid ethyl ester,

(e)2-(4-chlorophenyl)-4-diethylamino-6-methyl-1H-imidazo[4,5-c]pyridine-1-aceticacid ethyl ester,

(f) 2-(4-chlorophenyl)-4-methyl-1H-imidazo[4,5-c]pyridine-1-acetic acidethyl ester and

(g) 2-(4-chlorophenyl)-5-methoxy-3H-imidazo[4,5-b]pyridine-3-acetic acidethyl ester.

EXAMPLE 225(R)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid2-hydroxyethyl ester

A solution of (R)-N-[3-[(4-chlorobenzoyl)amino]-2-pyridinyl]alaninemethyl ester (27.4 g, 0.0822 mole) in ethylene glycol (150 ml) wasrefluxed under nitrogen for 1.75 hours and then cooled. One-third ofthis solution was added to water (1 liter), extracted with ethyl acetatetwice and the combined organic layers were washed three times with waterand once with a saturated sodium chloride solution. The organic layerwas dried over magnesium sulfate, treated with charcoal, filtered, andevaporated to give 8.3 g of a yellow solid (96% yield). The solid wasdissolved in hot isopropyl ether (with a little isopropyl alcohol) andfiltered hot. Upon cooling to room temperature, solid precipitated,which was collected by filtration, rinsed with isopropyl ether, anddried under high vacuum at room temperature to give 3.29 g of titlecompound, mp 110°-113° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₃ Cl: C, 59.05; H, 4.66; N, 12.15.Found: C, 59.00; H, 4.67; N, 12.15.

EXAMPLE 226(R)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid2-hydroxyethyl ester

A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.22 g, 0.014 mole) and concentratedsulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed undernitrogen for three hors, and then poured into a saturated sodiumbicarbonate solution (200 ml). Water (50 ml) was added and the productwas extracted into three portions of ethyl acetate. The combined organiclayers were washed twice with water and once with a saturated sodiumchloride solution, dried over magnesium sulfate, treated with charcoal,filtered, and evaporated under reduced pressure to give 2.6 g (54%yield) of an oily glass. The glass was dissolved in hot isopropyl ether(with a little isopropyl alcohol added), filtered while hot, and cooledto room temperature with stirring, causing a solid to precipitate. Themixture was cooled in the freezer, and the solid was collected byfiltration, rinsed with isopropyl ether and dried under high vacuum atroom temperature to give 1.60 g of title compound, mp. 110°-113° C.

Analysis: Calculated for C₁₇ H₁₆ N₃ O₃ Cl: C, 59.05; H, 4.66; N, 12.15.Found: C, 58.99; H, 4.66; N, 12.13.

EXAMPLE 227 2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanamide

A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoicacid (5.52 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183mole) was stirred at room temperature in dry tetrahydrofuran (100 ml)for 2.5 hours with a stream of nitrogen bubbling through it. Liquidammonia (50 ml) was added to the reaction mixture (cooled in dryice/acetone bath) and the mixture was allowed to warm to roomtemperature and was stirred for 2 days under nitrogen atmosphere. Thesolvents were removed under reduced pressure and the resulting solid wastriturated in water (100 ml), collected by filtration, rinsed twice withwater, twice with a 5% potassium hydroxide solution, and twice againwith water. The solid was recrystallized from hot methanol and driedunder high vacuum at 40° C. to give 2.86 g (52%) of title compound, mp.248°-250° C.

Analysis: Calculated for C₁₅ H₁₃ N₄ OCl: C, 59.90; H, 4.36; N, 18.63.Found: C, 59.66, H, 4.31; N, 18.57.

EXAMPLE 228 2-(5-Bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.90 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183mole) was stirred at room temperature in dry tetrahydrofuran (100 ml)for 2.5 hours with a stream of nitrogen bubbling through it. Thereaction mixture was cooled in a dry ice/acetone bath, and liquidammonia (50 ml) was added. The mixture was allowed to warm to roomtemperature and was stirred for 2 days under nitrogen atmosphere. Thesolvents were removed under reduced pressure and the resulting solid wastriturated in water (100 ml), collected by filtration, rinsed twice withwater, twice with a 5% potassium hydroxide solution and twice again withwater. The solid was recrystallized from hot methanol and dried underhigh vacuum at 40° C. to give 2.23 g (38%) of title compound, mp.>250°C.

Analysis: Calculated for C₁₂ H₉ N₄ O₂ Br: C, 44.88; H, 2.82; N, 17.45.Found: C, 44.79; H, 2.83; N, 17.39.

EXAMPLE 229 2-(5-Methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-aceticacid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183mole) was stirred at room temperature in dry tetrahydrofuran (100 ml)for 2.5 hours with a stream of nitrogen bubbling through it. Thereaction mixture was cooled in a dry ice/acetone bath, and liquidammonia (50 ml) was added. The mixture was allowed to warm to roomtemperature and was stirred for 2 days under nitrogen atmosphere. Thesolvents were removed under reduced pressure and the resulting solid wastriturated in water, collected by filtration, rinsed twice with water,twice with a 5% potassium hydroxide solution and twice again with water.The solid was recrystallized from hot methanol and dried under highvacuum at 40° C. to give 2.82 g (56%) of title compound, mp>250° C.

Analysis: Calculated for C₁₃ H₁₂ N₄ OS: C, 57.34; H, 4.44; N, 20.57.Found: C, 57.10; H, 4.39; N, 20.41.

EXAMPLE 2302-(4-Fluorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845mole) was stirred at room temperature in dry tetrahydrofuran (100 ml)for three hours with a stream of nitrogen bubbling through it. Asolution of methylamine in tetrahydrofuran (37 ml of a 3.03M solution,0.111 mole) was added and the reaction mixture was stirred at roomtemperature under nitrogen overnight. The solvents were removed underreduced pressure and the residue was triturated in water (100 ml). Thesolid was collected by filtration, rinsed twice with water, twice with a5% potassium hydroxide solution and twice again with water. The solidwas dissolved in hot isopropyl alcohol, filtered hot, cooled to roomtemperature and isopropyl ether was added to the cloud point. Theresulting solid was collected by filtration, rinsed with isopropylether, and dried under high vacuum at 42° C. overnight to give 2.30 g(44%) of title compound, mp. 215°- 217° C.

Analysis: Calculated for C₁₅ H₁₃ N₄ OF: C, 63.37; H, 4.61; N, 19.71.Found: C, 63.28; H, 4.60; N, 19.68.

EXAMPLE 2312-(4-Fluorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845mole) was stirred at room temperature in dry tetrahydrofuran (100 ml)for three hours with a stream of nitrogen bubbling through it. Asolution of dimethylamine in tetrahydrofuran (48 ml of 2.29M solution,0.111 mole) was added and the reaction mixture was stirred at 45° C.under nitrogen overnight. The solvents were removed under reducedpressure and the residue was triturated in water (100 ml), the solid wascollected by filtration, rinsed twice with water, twice with a 5%potassium hydroxide solution and twice again with water. The solid wasdissolved in hot isopropyl alcohol, filtered hot, cooled to roomtemperature and isopropyl ether was added to the cloud point. Theresulting solid was collected by filtration, rinsed with isopropyl etherand dried under high vacuum at 42° C. overnight to give 2.15 g (39%) oftitle compound, mp. 180°-183° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OF: C, 64.42; H, 5.07; N, 18.78.Found: C, 64.34; H, 5.14; N, 18.63.

EXAMPLE 2322-(4-Fluorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845mole) was stirred at room temperature in dry tetrahydrofuran (100 ml)for three hours with a stream of nitrogen bubbling through it. Asolution of dipropylamine (5.6 g, 0.0554 mole) in tetrahydrofuran (7 ml)was added and the reaction mixture was refluxed overnight undernitrogen. The solvents were removed under reduced pressure and theresidue was triturated in 100 ml of water, the solid was collected byfiltration, rinsed twice with water, twice with a 5% potassium hydroxidesolution and twice again with water. The solid was dissolved in hotisopropyl alcohol, filtered hot, cooled to room temperature, and waterwas added to the cloud point. The resulting solid was collected byfiltration, rinsed with water, and dried under high vacuum at 42° C.overnight to give 2.22 g (34%) of title compound, mp. 135°-136° C.

Analysis: Calculated for C₂₀ H₂₃ N₄ OF: C, 67.78; H, 6.54; N, 15.81.Found: C, 67.76; H, 6.56; N, 15.72.

EXAMPLE 233 2-(4-Fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:1]

A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(4.49 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole)was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5hours with a stream of nitrogen bubbling through it. The reactionmixture was cooled in a dry ice/acetone bath and liquid ammonia (50 ml)was added. The mixture was allowed to warm to room temperature and wasstirred overnight under nitrogen. The solvents were removed underreduced pressure and the resulting solid was triturated in water (100ml), collected by filtration, rinsed twice with water, twice with a 5%potassium hydroxide solution and twice with water. The solid wasdissolved in hot methanol, filtered while hot and cooled to roomtemperature. Water was added to the cloud point. The resulting solid wascollected by filtration, rinsed with water, and dried under high vacuumat room temperature to give 3.04 g (68%) of title compound, mp.246°-248° C.

Analysis: Calculated for C₁₄ H₁₃ N₄ O₂ F: C, 58.33; H, 4.54; N, 19.43.Fond: C, 58.30; H, 4.50; N, 19.38.

EXAMPLE 234(S)-2-(4-Chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of(S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4.5-b]pyridine-3-acetic acid(3.65 g, 0.012 mole) and 1,1'-carbonyldiimidazole (1.96 g, 0.0121 mole)was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5hours with a stream of nitrogen bubbling through it. The reactionmixture was cooled in a dry ice/acetone bath, liquid ammonia (50 ml) wasadded, the mixture was allowed to warm to room temperature and wasstirred overnight under nitrogen. The solvents were removed underreduced pressure and the resulting solid was partitioned between water(100 ml) and ethyl acetate (100 ml). The insoluble solid was collectedby filtration (1.38 g). The layers were separated, the aqueous layer wasextracted once with ethyl acetate and the combined organic layers werewashed twice with water, twice with a 5% potassium hydroxide solutionand twice again with water, dried over magnesium sulfate, treated withcharcoal, filtered, and evaporated under reduced pressure to give 1.9 gof solid. The 3.28 g (91 % yield) of solids were combined and dissolvedin hot methanol, filtered hot, cooled to room temperature and water wasadded to the cloud point. The resulting solid was collected byfiltration, rinsed with water and dried under high vacuum at roomtemperature to give 2.50 g of title compound, mp. 202°-204° C.

Analysis: Calculated for C₁₅ H₁₃ N₄ OCl: C, 59.90; H, 4.36; N, 18.63.Found: C, 59.85; H, 4.34; N, 18.44.

EXAMPLE 235 2-(4-Bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A mixture of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid(5.51 g, 0.0166 mole) and 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole)was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5hours with a stream of nitrogen bubbling through it. The reactionmixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml)was added. The mixture was allowed to warm to room temperature and wasstirred overnight under nitrogen. The solvents were removed underreduced pressure and the resulting solid was triturated in water (100ml), collected by filtration, and rinsed twice with water, twice with a5% potassium hydroxide solution and twice again with water. The solidwas dissolved in hot methanol, filtered while hot, and cooled to roomtemperature. The resulting solid was collected by filtration and driedunder high vacuum at room temperature to give 3.00 g (54%) of titlecompound, mp>250° C.

Analysis: Calculated for C₁₄ H₁₁ N₄ OBr: C, 50.78; H, 3.35; N, 16.92.Found: C, 50.63; H, 3.32; N, 16.84.

EXAMPLE 2362-[2-(4-Chlorophenyl)-1H-imidazo[4,5-b]pyridin-1-yl]-1-phenylethanone

Under nitrogen atmosphere, the2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (5.0 g, 0.022 mole) wasadded to a suspension of sodium hydride (0.96 g of 60% in oil, 0.024mole, washed once with hexanes) in dimethylformamide (100 ml). Themixture was heated at 70°-85° C. for 1.5 hr before adding theα-bromoacetophenone (4.38 g, 0.022 mole) at room temperature. Thereaction mixture was stirred at room temperature overnight, then pouredinto water. The precipitate was collected by filtration, washed withwater, and dried under high vacuum. A sample was dissolved in isopropylalcohol, then concentrated to initiate crystallization. The crystalswere collected by filtration, washed with isopropyl alcohol, and driedunder high vacuum at 70° C. over a weekend to give 1.5 g (20%) of titlecompound, mp. 262°-263° C.

Analysis: Calculated for C₂₀ H₁₄ N₃ OCl: C, 69.07; H, 4.06; N, 12.08.Found: C, 68.78; H, 4.03; N, 12.02.

EXAMPLE 2372-(4-Chlorophenyl)-α-phenyl-3H-imidazo[4,5-b]pyridine-3-ethanol

4-Chloro-N-[2-[(2-hydroxy-2-phenylethyl)amino]-3-pyridinyl]benzamide(13.2 g, 0.036 mole) was heated at 180°-190° C. in a glass flask on aWood's metal bath for 12 minutes. The residue was dissolved in ethylacetate, treated with Florisil®, and filtered. The filtrate was dilutedwith hexanes to initiate crystallization. The solid was collected byfiltration, washed with ethyl acetate/hexanes mixture and then hexane.The solid still contained 10-15% uncyclized material, and therefore aportion of the solid (1.25 g) was heated at 180°-190° C. for anadditional 17 minutes. The solid residue was recrystallized frommethylene chloride/hexane and dried under high vacuum at 70° C.overnight to give 0.8 g of solid, mp. 166°-168° C.

Analysis: Calculated for C₂₀ H₁₆ N₃ OCl: C, 68.67; H, 4.61; N, 12.01.Found: C, 68.46; H, 4.54; N, 12.02.

EXAMPLE 2382-[2-(4-Chlorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]-1-phenyl ethanone

Under nitrogen atmosphere, a solution of2-(4-chlorophenyl)-α-phenyl-3H-imidazo[4,5-b]pyridine-3-ethanol (9.44 g,0.027 mole) in methylene chloride (50 ml) was added to a stirredsuspension of pyridinium chlorochromate (8.75 g, 0.041 mole) inmethylene chloride (100 ml) and allowed to stir at room temperatureovernight. The reaction mixture was filtered. The residue was treatedwith boiling methylene chloride and filtered. The methylene chloridefiltrate was treated with Florisil® and filtered. The filtrate wasevaporated to dryness and the residue was recrystallized from isopropylalcohol. The crystals were collected by filtration, washed withisopropyl alcohol/water, and dried under high vacuum overnight at roomtemperature to give 5.0 g (54%) of title compound, mp. 211°-212.5° C.

Analysis: Calculated for C₂₀ H₁₄ N₃ OCl: C, 69.07; H, 4.06; N, 12.08.Found: C, 68.92; H, 4.02; N, 12.09.

EXAMPLE 2392-(4-Chlorophenyl)-N,N-dimethyl-1H-imidazo[4,5-c]pyridine-1-acetamide

CrudeN-[3-[bis(4-chlorobenzoyl)amino]-4-pyridinyl]N,N-dimethyl-glycinamide(9.24 g) obtained by evaporating the final filtrate of preparation 50was heated in a glass flask in a Wood's metal bath at 180°-190° C. for10 minutes. The residue was dissolved in methylene chloride andextracted with dilute aqueous sodium hydroxide (3x). The aqueous basiclayers were combined and extracted with methylene chloride. Themethylene chloride layers were combined, dried, and evaporated. Theresidue was purified by flask chromatography (375 g) eluting first withethyl acetate (5.5 liters) followed by 90% ethyl acetate/10% methylalcohol, and finally 80% ethyl acetate/20% methyl alcohol. The desiredproduct, which was contained in the latter fractions, were combined andevaporated. The solid was recrystallized from isopropylalcohol/isopropyl ether to give 1.4 g (24%) of solid, mp. 236°-238° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OCl: C, 61.05; H, 4.80; N, 17.80.Found: C, 60.61; H, 4.86; , 17.49.

EXAMPLE 2405-Chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid

A solution of N-[6-chloro-3-[(4-chlorobenzoyl)amino]-2-pyridinyl]glycineethyl ester (1.7 g, 0.00462 mole) in ethylene glycol (25 ml) wasrefluxed under nitrogen for two hours. To one-half of the solution(0.0023 mole) was added water (2 ml) and solid potassium hydroxide (0.20g, 0.003515 mole) and the mixture was refluxed for an additional 15minutes, poured into ice water (100 ml) and acidified with 3Nhydrochloric acid solution. The resulting solid was collected byfiltration, rinsed with water, dissolved in hot methanol and filteredhot. Addition of water to the cloud point and cooling to roomtemperature gave a solid which was collected by filtration, washed withwater, and dried at 60° C. under high vacuum to give 0.4 g (54% yield)of title compound, mp >250° C.

Analysis: Calculated for C₁₄ H₉ N₃ O₂ Cl₂ : C, 52.20; H, 2.82; N, 13.04.Found: C, 52.22; H, 2.79; N, 13.00.

EXAMPLE 2415-Chloro-2-(4-chlorophenyl)-N,N-dipropyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A suspension of5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1g, 0.00963 mole) and 1,1'-carbonyldiimidazole (1.56 g, 0.00963 mole) intetrahydrofuran (100 ml) was refluxed for 3.25 hours under nitrogen,cooled to room temperature, a stream of nitrogen was bubbled through thesolution for 0.75 hr then a solution of dipropylamine (2.92 g, 0.0289mole) in tetrahydrofuran (4 ml) was added. The reaction mixture wasrefluxed overnight under nitrogen and evaporated under reduced pressure.The residue was partitioned between water and ethyl acetate, the layerswere separated, sodium chloride was added to the aqueous layer and itwas re-extracted with ethyl acetate. The combined organic layers werewashed twice with a saturated sodium chloride solution, dried overmagnesium sulfate, charcoaled, filtered and evaporated under reducedpressure to a solid (3.7 g, 95% yield). The solid was recrystallizedfrom isopropyl alcohol/water and dried under high vacuum at 58° C. togive 2.11 g of title compound, mp 170°-173.5° C.

Analysis: Calculated for C₂₀ H₂₂ N₄ OCl₂ : C, 59.27; H, 5.47; N, 13.82.Found: C, 59.09; H, 5.43; N, 13.79.

EXAMPLE 2425-Chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:1]

A suspension of 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.00963 mole) and1,1'-carbonyldiimidazole (1.56 g, 0.00963 mole) in tetrahydrofuran (100ml) was refluxed under nitrogen for 1.5 hours, cooled to roomtemperature, and a stream of nitrogen, was bubbled through the solutionfor one hour. The solution was cooled in a dry ice/acetone bath andliquid ammonia (50 ml) was added. The reaction mixture was allowed towarm to room temperature and was stirred at room temperature for twodays. The solvents were removed under reduced pressure and the solid wastriturated in water (100 ml), collected by filtration, and rinsed twicewith water, twice with a 5% potassium hydroxide solution, and twiceagain with water. The solid was recrystallized twice from isopropylalcohol/water and dried under high vacuum at 70° C. to give 1.78 g (54%)of title compound, mp>250° C.

Analysis: Calculated for C₁₄ H₁₂ N₄ O₂ Cl₂ : C, 49.58; H, 3.57; N,16.52. Found: C, 49.86; H, 3.50; N, 16.55.

EXAMPLE 2435-Chloro-2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamidehydrate [1:0.5]

A suspension of 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.1 g, 0.00963 mole) and1,1'-carbonyldiimidazole (1.56 g, 0.00963 mole) in tetrahydrofuran (100ml) was refluxed under nitrogen for 3.25 hours, cooled to roomtemperature and a stream of nitrogen was bubbled through the solutionfor 0.75 hours. A solution of dimethylamine in tetrahydrofuran (21.9 mlof a 2.65M solution, 0.0578 mole) was added and the solution was stirredat 50° C. under nitrogen overnight. The solvents were evaporated underreduced pressure, the residue was triturated in water (50 ml), collectedby filtration, and rinsed twice with water, twice with a 5% potassiumhydroxide solution and twice again with water. The resulting solid wasrecrystallized from isopropyl alcohol/water to give 1.70 g of solid (50%yield) which was dissolved in hot isopropyl alcohol, treated withcharcoal, filtered while hot and brought to the cloud point by additionof water. Cooling to room temperature gave a solid which was collectedby filtration and dried under high vacuum at 70° C. to give 1.05 g titlecompound, mp 203°-205° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ O₁.5 Cl₂ : C, 53.65; H, 4.22; N,15.64. Found: C, 53.71; H, 3.95; N, 15.62.

EXAMPLE 2442-(4-Bromophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetamide

Under a nitrogen atmosphere, oxalyl chloride (2.6 g, 0.020 mole) wasadded dropwise (slowly) to a stirred and chilled (5°-10° C.) suspensionof 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.4 g,0.019 mole) in anhydrous dimethylformamide (50 ml). The reaction mixturewas heated at 55°-60° C. for 5 hours, cooled to room temperature, andadded dropwise to a stirred and chilled (10°-15° C.) suspension ofN,N-dimethyl-p-phenylenediamine dihydrochloride (4.04 g, 0.0193 mole),triethylamine (8.2 g, 0.081 mole), and anhydrous dimethylformamide (100ml). The reaction mixture was stirred overnight at room temperature,filtered, and poured into ice water (500 ml). The mixture was allowed toprecipitate, and filtered. The filter cake was triturated in potassiumbicarbonate solution (100 ml), filtered, and rinsed with water (100 ml).The cake was twice recrystallized from tetrahydrofuran/ethyl alcohol,giving 2.8 g (31%) of a white solid, mp 248°- 250° C.

Analysis: Calculated for C₂₂ H₂₀ N₅ OBr: C, 58.68; H, 4.48; N, 15.55.Found: C, 58.58; H, 4.41; N, 15.51.

EXAMPLE 245 2-(4-Chlorophenyl)-N-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]-pyridine-3-propanamide

Under a nitrogen atmosphere, oxalyl chloride (1.75 g, 0.0138 mole) wasadded dropwise, slowly, to a stirred and chilled (10° C.) suspension of2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (4.0 g,0.0133 mole) in anhydrous dimethylformamide (20 ml). A yellow solidformed. The suspension was stirred at room temperature for a few minutesand then a solution of N,N-dimethylphenylenediamine (2.0 g, 0.0147 mole)in dimethylformamide (25 ml) was added. The resulting purple solutionwas stirred at room temperature overnight under a nitrogen atmosphere.The reaction mixture was poured into 150 ml of water and stirred at roomtemperature. Triethylamine (2.0 ml) was added to pH 8 and a solidprecipitated. The solid was collected by filtration, dissolved in hotisopropyl alcohol, treated with charcoal, and filtered. Addition ofwater and cooling to room temperature caused a solid to form. The solidwas collected by filtration and rinsed with water to give 1.1 g of solid(20% yield). Drying under high vacuum at room temperature and then at80° C. gave a grayish solid, mp 216°-218° C.

Analysis: Calculated for C₂₃ H₂₂ N₅ OCl₁ : C, 65.79; H, 5.28; N, 16.68.Found: C, 65.60; H, 5.38N, 16.49.

EXAMPLE 2465-Chloro-2-(4-chlorophenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A solution of5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid 5.0g, 0.0155 mole) and 1,1'-carbonyldiimidazole (2.52 g, 0.0155 mole) indry tetrahydrofuran (100 ml) was refluxed under nitrogen for two hours.The solution was cooled to room temperature and a stream of nitrogen wasbubbled through it for thirty minutes. A solution of methylamine intetrahydrofuran (36 ml of a 2.59M solution, 0.0932 mole) was added andthe suspension was stirred at room temperature under nitrogen for threedays. The solvents were evaporated under reduced pressure and theresulting solid was triturated in water (100 ml), collected byfiltration, and rinsed twice with water, twice with a 5% potassiumhydroxide solution and twice again with water. The solid was dissolvedin hot isopropyl alcohol, dried over magnesium sulfate, treated withcharcoal and filtered while hot. The filtrate was reduced to one-halfits original volume and isopropyl ether was added. Upon cooling to roomtemperature, solid precipitated, which was collected by filtration,rinsed with isopropyl ether and dried under high vacuum at 60° C. togive 3.45 g (66% yield) of title compound, mp>250° C.

Analysis: Calculated for C₁₅ H₁₂ N₄ OCl₂ : C, 53.75; H, 3.61; N, 16.71.Found: C, 53.83; H, 3.60; N, 16.76.

EXAMPLE 2475-Chloro-2-(4-methylphenyl)-N-methyl-3H-imidazo[4,5-b]pyridine-3-acetamide

A slurry of5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.8g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionylchloride (1.22 g, 0.0102 mole) was added dropwise to the stirredsuspension. After stirring at room temperature for twenty minutes, thesolution was cooled again in an ice bath and a solution of methylaminein tetrahydrofuran (21.5 ml of a 2.59M solution, 0.056 mole) was addeddropwise. The suspension wa stirred at room temperature under nitrogenfor one hour and then the solvents were removed under reduced pressure.The residue was triturated in water (100 ml) and the resulting solid wascollected by filtration and rinsed three times with water. The solid wasdissolved in hot isopropyl alcohol, filtered while hot, and brought tothe cloud point with isopropyl ether. Upon cooling, a solid precipitatedwhich was collected by filtration, rinsed with isopropyl ether, anddried under high vacuum at 70° C. give 1.86 g (64% yield) of titlecompound, mp>250° C.

Analysis: Calculated for C₁₆ H₁₅ N₄ OCl: C, 61.05; H, 4.80; N, 17.80.Found: C, 61.01; H, 4.74; N, 17.68.

EXAMPLE 2485-Chloro-N,N-dimethyl-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide

A slurry of5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.8g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionylchloride (1.22 g, 0.0102 mole) was added dropwise to the stirredsuspension. After stirring at room temperature for twenty minutes, thesolution was cooled again in an ice bath and a solution of dimethylaminein tetrahydrofuran (18.9 ml of a 2.95M solution, 0.056 mole) was addeddropwise. The suspension was stirred at room temperature under nitrogenfor one hour and then the solvents were removed under reduced pressure.The residue was triturated in water (100 ml) and the resulting solid wascollected by filtration and rinsed three times with water. The solid wasdissolved in hot isopropyl alcohol, filtered while hot, and brought tothe cloud point with water. Upon cooling, a solid precipitated which wascollected by filtration, rinsed with water, and dried under high vacuumat 70° C. to give 2.17 g (71% yield) of title compound, mp 182°-185° C.

Analysis: Calculated for C₁₇ H₁₇ N₄ OCl: C, 62.10; H, 5.21; N, 17.04.Found: C, 61.70; H, 5.12; N, 16.80.

                                      TABLE 1                                     __________________________________________________________________________     ##STR41##                                                                     No.Ex.                                                                            (Z).sub.1-2 -A                                                                           Ar                                                                                      ##STR42##                                                                            B     W               IsomerOpt.*                                                                       Salt               __________________________________________________________________________    1   [4,5-b]pyridine-3H                                                                       4-Cl-pyridin-2-                                                                         CH.sub.2                                                                             C(O)  OH              --  --                                 yl                                                             2   [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OH              --  --                  3   [4,5-b]pyridine-3H                                                                       2-ClC.sub. 6 H.sub.4                                                                    CH.sub.2                                                                             C(O)  OH              --  --                  4   [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              C(O) OH              --  --                  5   [4,5-b]pyridine-3H                                                                       3-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  OH              --  --                  6   [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OH              --  --                  7   [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  OH              --  --                  8   [4,5-b]pyridine-3H                                                                       3-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OH              --  --                  9   [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  OH              --  --                  10  [4,5-b]pyridine-3H                                                                       3-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  OH              --  --                  11  [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  OH              --  --                  12  [4,5-b]pyridine-3H                                                                       3,4-Cl.sub.2C.sub.6 H.sub.3                                                             CH.sub.2                                                                             C(O)  OH              --  --                  13  [4,5-b]pyridine-3H                                                                       4-OCH.sub.3C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)  OH              --  --                  14  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  OH              --  --                  15  [4,5-b]pyridine-1H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OH              --  H.sub.2 O           16  [4,5-b]pyridine-3H                                                                       5-Br-furan-2-yl                                                                         CH.sub.2                                                                             C(O)  OH              --  --                  17  [4,5-b]pyridine-3H                                                                       4-NO.sub.2C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  OH              --  H.sub.2 O           18  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR43##                                                                           C(O)  OH              (S) --                  19  [4,5-b]pyridine-3H                                                                       C.sub.6 H.sub.5                                                                         CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  20  [4,5-b]pyridine-3H                                                                       C.sub.6 H.sub.5                                                                         CH.sub.2                                                                             C(O)  NH.sub.2        --  --                  21  [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  NH.sub.2        --  --                  22  [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  OC.sub. 2 H.sub.5                                                                             --  --                  23  [4,5-b]pyridine-3H                                                                       4-Cl-pyridin-                                                                           CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                                 2-yl                                                           24  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  25  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  26  [4,5-b]pyridine-3H                                                                       4-OCH.sub.3C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  27  [4,5-b]pyridine-3H                                                                       2-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  28  [4,5-b]pyridine-3H                                                                       2-OCH.sub.3C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  HCl                 29  [4,5-b]pyridine-3H                                                                       4-Cl-pyridin-2-                                                                         CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-                                                                        --  --                                 yl                     1-yl                                    30  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                  31  [4,5-b]pyridine-3H                                                                       2-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  HCl                 32  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-                                                                        --  1.5                                                       1-yl                fumarate            33  [4,5-b]pyridine-3H                                                                       3-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-                                                                        --  1.5                                                       1-yl                fumarate            34  [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-                                                                        --  fumarate                                                  1-yl                                    35  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-                                                                        --  fumarate                                                  1-yl                                    36  [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-                                                                        --  fumarate                                                  1-yl                                    37  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub. 2       --  fumarate            38  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  OC.sub.2 H.sub.5                                                                              --  --                  39  [4,5-b]pyridine-3H                                                                       3-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  40  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  morpholin-4-yl  --  --                  41  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(CH.sub.2).sub.2N                                                                           --  --                                                        (CH.sub.3).sub.2                        42  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(CH.sub.2).sub.2N                                                                           --  2HCl                                                      (CH.sub.3).sub.2                        43  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(-pyridin-3-yl                                                                              --  0.5 H.sub.2 O       44  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(-pyridin-3-yl                                                                              --  2 HCl                                                                         1.5 H.sub.2 O       45  [4,5-b]pyridine-3H                                                                       3-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-                                                                        --  1.5                                                       1-yl                fumarate            46  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  4-(3-CF.sub.3C.sub.6 H.sub.4)-                                                                --  --                                                        piperazin-1-yl                          47  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHCH.sub.3      --  --                  48  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  49  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  HCl                 50  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  OC.sub.2 H.sub.5                                                                              --  HCl                 51  [4,5-b]pyridine-3H                                                                       2-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  OC.sub.2 H.sub.5                                                                              --  HCl                 52  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OC(CH.sub.3).sub.3                                                                            --  --                  53  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(S)  NH.sub.2        --  0.5 H.sub.2 O       54  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OCH.sub.3       --  --                  55  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OCH(CH.sub.3).sub.2                                                                           --  --                  56  [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  57  [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  4-CH.sub.3 -piperazin-1-yl                                                                    --  fumarate            58  [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  OCH.sub.3       --  HCl                 59  [4,5-b]pyridine-3H                                                                       3-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(CH.sub. 3).sub.2                                                                            --  --                  60  [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  NHCH.sub.3      --  --                  61  [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  OC(CH.sub.3).sub.3                                                                            --  --                  62  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  63  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHCH.sub.3      --  HCl                 64  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(C.sub.2 H.sub.5).sub.2                                                                      --  0.5 H.sub.2 O       65  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[CH(CH.sub.3).sub.2 ]                                                                       --  --                  66  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[1-C.sub.2 H.sub.5 -                                                                        --  2 HCl                                                     piperidin-2-yl]     H.sub.2 O           67  [4,5-b] pyridine-1H                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  CH.sub.3        --  HCl                 68  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[CH.sub.2 C(O)                                                                              --  --                                                        OC.sub.2 H.sub.5 ]                      69  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHC.sub.3 H.sub.7                                                                             --  --                  70  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[CH.sub.2 C(O)                                                                              --  --                                                        OC.sub.2 H.sub.5 ]                      71  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[CH.sub.2 -[(1-                                                                             --  2 HCl                                                     C.sub.2 H.sub.5)-pyrroli-                                                     din-2-yl]]                              72  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHCH.sub.2 C(O)OK                                                                             --  **2 H.sub.2 O       73  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHC.sub.6 H.sub.5                                                                             --  --                  74  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(1-C.sub.2 H.sub.5)-                                                                       --  2 HCl                                                     pyrrolidin-         H.sub.2 O                                                 3-yl]                                   75  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3 -                                                                         --  --                                                        C(O)OC.sub.2 H.sub.5 ]                  76  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(pyridin-3-   --  2 HCl                                                     yl)                                     77  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3                                                                           --  2 HCl                                                     N(CH.sub.3).sub.2 ]                     78  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[CH.sub.2 -(1-                                                                              --  2 HCl                                                     C.sub.2 H.sub.5)-pyrroli-                                                     din-2-yl]                               79  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(1-ethyl)-   --  HCl                                                       piperidin-3-yl)]                        80  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[4-N(CH.sub.3).sub.2                                                                        --  HCl                                                       C.sub.6 H.sub.4]                        81  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(1-piperi-    --  HCl                                                       dinylethyl-)        0.5 H.sub.2 O       82  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3                                                                           --  2 HCl                                                     N(CH.sub.3).sub.2 ] H.sub.2 O           83  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2NHC                                                                        --  0.5 H.sub.2 O                                             (O)CH.sub.3 ]                           84  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3C(O)                                                                       --  --                                                        OC.sub.2 H.sub.5 ]                      85  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2 N                                                                         --  --                                                        (CH.sub.3).sub.2 ]                      86  [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                          1-piperidinyl                                                                     --         --                                                             87  [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  88  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(CH.sub.2 CHCH.sub.2)                                                                       --  --                  89  [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  90  [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)   NHCH.sub.3     --  --                  91  [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHCH.sub.3      --  HCl                 92  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3                                                                           --  **H.sub.2 O                                               C(O)OK                                  93  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                          1-piperidinyl                                                                     --         --                                                             94  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHCH.sub.2 C.sub.6 H.sub.5                                                                    --  --                  95  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHC.sub.3 H.sub.5                                                                             --  --                  96  [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  1-pyrrolidinyl  --  --                  97  [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(1-ethyl)-   --  --                                                        pyrrolidin-                                                                   3-yl                                    98  [ 4,5-b]pyridine-3H                                                                      4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(1-ethyl)-   --  HCl                                                       pyrrolidin-         H.sub.2 O                                                 3-yl]                                   99  [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     (CH.sub.2)                                                                           C(O)  NH(1-piperi-    --  --                                                        dinylethyl-)                            100 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     (CH.sub.2)                                                                           C(O)  NH(1-piperi-    --  2 HCl                                                     dinylethyl-)        H.sub.2 O           101 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(1-ethyl-    --  --                                                        piperidin-                                                                    3-yl]                                   102 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(1-ethyl-    --  2 HCl                                                     piperidin-          H.sub.2 O                                                 3-yl]                                   103 [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[ CH.sub.2 C(O)OK]                                                                          --  **2 H.sub.2 O       104 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(pyridin-2-   --  --                                                        yl)                                     105 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHC.sub.5 H.sub.9                                                                             --  --                  106 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(CH.sub.2C.sub.3 H.sub.5)                                                                   --  --                  107 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHC.sub.6 H.sub.11                                                                            --  --                  108 [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(1-ethyl)-   --  2 HCl                                                     pyrrolidin-3-yl]    0.5 H.sub.2 O       109 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2                                                                           --  --                                                        N(CH.sub.3).sub.2 ]                     110 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2                                                                           --  2 HCl                                                     N(CH.sub.3).sub.2 ] 0.5 H.sub.2 O       111 [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHC.sub.6 H.sub.5                                                                             --  --                  112 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(2-ClC.sub.6 H.sub.4)                                                                       --  --                  113 [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(1-piperi-    --  --                                                        dinylethyl-)                            114 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                          1-piperidinyl                                                                     --         --                                                             115 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NCH.sub.3 (CH.sub.2                                                                           --  --                                                        C.sub.6 H.sub.5)                        116 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(2-ClC.sub.6 H.sub.4)                                                                       --  --                  117 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(pyridin-3-   --  2 HCl                                                     yl)                                     118 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(pyridin-3-   --  0.5 H.sub.2 O                                             yl)                                     119 [4,5-b]pyridine-3H                                                                       pyridin-2-yl                                                                            CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  HCl                                                                           0.5 H.sub.2 O       120 [4,5-b]pyridine-3H-                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      4-oxide                                                                   121 [4,5-b]pyridine-3H-                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      4-oxide                                                                   122 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(C.sub.4 H.sub.9                                                                             --sub.2                                                                           --                  123 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(pyridin-2-yl)                                                                              --  --                  124 [4,5-b] pyridine-3H                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.2 CHCH.sub.2).sub.2                                                                  --  --                  125 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHC.sub.6 H.sub.5                                                                             --  --                  126 [4,5-b]pyridine-3H                                                                       3-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NHCH.sub.3      --  --                  127 [4,5-b]pyridine-3H                                                                       3-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  128 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  129 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  NH(CH.sub.2 C.sub.6 H.sub.5)                                                                  --  --                  130 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[4-N(CH.sub.3).sub.2                                                                        --  2HCl                                                      C.sub.6 H.sub.4]    1.5 H.sub.2 O       131 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(CH.sub.3)(C.sub.6 H.sub.5)                                                                  --  --                  132 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(C.sub.2 H.sub.5).sub.2                                                                      --  --                  133 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(CH.sub.3)     --  0.5 H.sub.2 O                                             (CH.sub.2 C.sub.6 H.sub.5)              134 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N[CH(CH.sub.3).sub.2 ].sub.2                                                                  --  --                  135 [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  0.5 H.sub.2 O       136 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(C.sub.4 H.sub.9).sub.2                                                                      --  --                  137 [4,5-b]pyridine-3H                                                                       3-ClC.sub. 6 H.sub.4                                                                    CH.sub.2                                                                             C(O)  NH(pyridin-     --  --                                                        2-yl)                                   138 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3)(C.sub.6 H.sub.5)                                                                  --  --                  139 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[4-N(CH.sub.3).sub.2                                                                        --  --                                                        C.sub.6 H.sub.4]                        140 [4,5-b]pyridine-3H                                                                       4-OCH.sub.3C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  141 [4,5-b]pyridine-3H                                                                       3,4-Cl.sub.2C.sub.6 H.sub.3                                                             CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  142 [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3                                                                           --  0.5 H.sub.2 O                                             COOH]                                   143 [4,5-b]pyridine-3H                                                                       4-OCH.sub.3C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)   N(C.sub.3 H.sub.7).sub.2                                                                     --  --                  144 [4,5-b]pyridine-3H                                                                       4-OCH.sub.3C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)                                          1-piperidinyl                                                                     --         --                                                             145 [4,5-b]pyridine-3H                                                                       4-OCH.sub.3C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)  N(C.sub.2 H.sub.5).sub.2                                                                      --  0.5 H.sub.2 O       146 [4,5-b]pyridine-3H                                                                       3,4-Cl.sub.2C.sub.6 H.sub.3                                                             CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  0.5 H.sub.2 O       147 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  148 [4,5-b]pyridine-3H                                                                       3-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                          1-piperidinyl                                                                     --         --                                                             149 [4,5-b]pyridine-3H                                                                       3-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  150 [4,5-b]pyridine-3H                                                                       3-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NCH.sub.3       --  --                                                        [CH.sub.2 CH.sub.2 CH.sub.2                                                                   --  --                                                        [(4-CH.sub.3)-                                                                piperazin-1-yl]]                        151 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2 OCH.sub.3                                                                 --  --                  152 [4,5-b]pyridine-3H                                                                       3,4-Cl.sub.2C.sub.6 H.sub.3                                                             CH.sub.2                                                                             C(O)  1-piperidinyl   --  --                  153 [4,5-b]pyridine-3H                                                                       3,4-Cl.sub.2C.sub.6 H.sub.3                                                             CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2                                                                           --  2 HCl                                                     N(CH.sub.3).sub.2 ]                     154 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(C.sub.6 H.sub.5).sub.2                                                                      --  --                  155 [4,5-b]pyridine-3H                                                                       4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2                                                                           --  --                                                        N(CH.sub.3).sub.2 ]                     156 [4,5-b]pyridine-3H                                                                       4-CF.sub.3 C.sub.6 H.sub.4                                                              CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2                                                                           --  2 HCl                                                     N(CH.sub.3).sub.2 ]                     157 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  158 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  NH[(CH.sub.2).sub.2                                                                           --  2 HCl                                                     N(CH.sub.3).sub.2 ]                     159 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  NH[(CH.sub.2).sub.2                                                                           --  --                                                        N(CH.sub.3).sub.2 ]                     160 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  1-azetidinyl    --  --                  161 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  NH[4-N(CH.sub.3).sub.2                                                                        --  2 HCl                                                     C.sub.6 H.sub.4]                        162 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2                                                                           --  --                                                        N(C.sub.2 H.sub.5).sub.2 ]              163 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.2                                                                           --  2 HCl                                                     N(C.sub.2 H.sub.5).sub.2 ]                                                                        0.5 H.sub.2 O       164 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3                                                                           --  --                                                        N(C.sub.2 H.sub.5).sub.2 ]              165 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[(CH.sub.2).sub.3                                                                           --  2 HCl                                                     N(C.sub.2 H.sub.5).sub.2 ]              166 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR44##      --  --                  167 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  N(CH.sub.3).sub.2                                                                             --  HCl                 168 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  N(CH.sub.3)(C.sub.6 H.sub.5)                                                                  --  HCl                 169 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR45##      --  --                  170 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR46##      --  --                  171 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR47##                                                                           C(O)  N(CH.sub.3).sub.2                                                                             (S) --                  172 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR48##                                                                           C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      (S) --                  173 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR49##                                                                           C(O)  N(CH.sub.3)(C.sub.6 H.sub.5)                                                                  (S) --                  174 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NCH.sub.3 [(CH.sub.2).sub.2                                                                   --  --                                                        N(CH.sub.3).sub.2 ]                     175 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NCH.sub.3 [(CH.sub.2).sub.2                                                                   --  2 HCl                                                     N(CH.sub.3).sub.2 ]                     176 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR50##                                                                           C(O)  NH[(CH.sub.2).sub.2 N(CH.sub.3).sub.                                          2 ]             (S) --                  177 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR51##                                                                           C(O)  NH[(CH.sub.2).sub.2 N(CH.sub.3).sub.                                          2 ]             (S) 2 HCl 0.5                                                                     H.sub.2 O           178 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NCH.sub.3 (CH.sub.2 CHCH.sub.2)                                                               --  --                  179 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR52##      --  2 HCl 0.5                                                                     H.sub.2 O           180 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR53##      --  2 HCl H.sub.2                                                                 O                   181 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR54##      --  2 HCl H.sub.2                                                                 O                   182 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR55##      --  --                  183 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3)[4-N(CH.sub.3).sub.2                                                               --  --                                                        C.sub.6 H.sub.4]                        184 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3)[4-N(CH.sub.3).sub.2                                                               --  2 HCl                                                     C.sub.6 H.sub.4]    2.5 H.sub.2 O       185 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR56##      --  --                  186 [4,5-b]pyridine-1H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              C(O) N(C.sub.3 H.sub.7).sub.2                                                                      --  0.5 H.sub.2 O       187 [4,5-b]pyridine-1H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  HCl                 188 [4,5-b]pyridine-1H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                  189 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  190 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR57##      --  0.5 H.sub.2 O       191 [4,5-b]pyridine-3H                                                                       4-NO.sub.2C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  192 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR58##                                                                           C(O)  OC.sub.2 H.sub.5                                                                              (S) --                  193 [4,5-b] pyridine-3H                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR59##      --  --                  194 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)                                                                                 ##STR60##      --  --                  195 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[4-[N(CH.sub.3).sub.2 ]                                                                     --  H.sub.2 O                                                 C.sub.6 H.sub.4]                        196 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[3-[N(CH.sub.3).sub.2 ]                                                                     --  2 HCl                                                     C.sub.6 H.sub.4]    0.5 H.sub.2 O       197 [4,5-b]pyridine-3H                                                                       4-NO.sub.2C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  198 [4,5-b]pyridine-3H                                                                       4-NO.sub.2C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  NHCH.sub.3      --  --                  199 [4,5-b]pyridine-3H                                                                       5-Br-furan-2-yl                                                                         CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  0.5 H.sub.2 O       200 [4,5-b]pyridine-3H                                                                       5-Br-furan-2-yl                                                                         CH.sub.2                                                                             C(O)  NHCH.sub.3      --  --                  201 [4,5-b]pyridine-3H                                                                       4-NO.sub.2C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  202 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3)(C.sub.3 H.sub.7)                                                                  --  2 H.sub.2 O         203 [4,5-b]pyridine-3H                                                                       5-Br-furan-2-yl                                                                         CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  204 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR61##                                                                           C(O)  NHCH.sub.3      (R) --                  205 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR62##                                                                           C(O)  NHCH.sub.3      (S) --                  206 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR63##                                                                           C(O)  NH[4-N(CH.sub.3).sub.2 C.sub.6                                                H.sub.4]        (S) 2 HCl H.sub.2                                                                 O                   207 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR64##                                                                           C(O)  N(CH.sub.3).sub.2                                                                             (R) --                  208 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR65##                                                                           C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      (R) --                  209 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  CH.sub.3        --  --                  210 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR66##                                                                           C(O)  O(CH.sub.2).sub.2 OH                                                                          (R) HCl                 211 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR67##                                                                          CH.sub.3        Rac HCl                 212 [4,5-b]pyridine-3H                                                                       5-CH.sub.3 -thiophen-                                                                   CH.sub.2                                                                             C(O)  OH              --  --                                 2-yl                                                           213 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR68##                                                                           C(O)  OC.sub.2 H.sub.4 OH                                                                           (S) --                  214 [4,5-b]pyridine-3H                                                                       5-CH.sub.3 -thiophen-                                                                   CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                                 2-yl                                                           215 [4,5-b]pyridine-3H                                                                       5-CH.sub.3 -thiophen-                                                                   CH.sub.2                                                                             C(O)  NHCH.sub.3      --  --                  216 [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.4 OH                                                                           --  --                  217 [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  218 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR69##                                                                           C(O)  OH              (R) --                  219 [4,5-b]pyridine-3H                                                                       5-CH.sub.3 -thiophen-                                                                   CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                                 2-yl                                                           220 [4,5-b]pyridine-3H                                                                       5-Br-furan-2-yl                                                                         CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                  221 [4,5-b]pyridine-3H                                                                       5-CH.sub.3 -thiophen-                                                                   CH.sub.2                                                                             C(O)  OC.sub.2 H.sub.5                                                                              --  --                                 2-yl                                                           222(a)                                                                            7-Cl[4,5-b]pyridine-                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      1H                                                                            7-Cl[4,5-b]pyridine-                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      3H                                                                          (b)                                                                             6-Cl[4,5-b]pyridine-                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      1H                                                                            6-Cl[4,5-b]pyridine-                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      3H                                                                        222(c)                                                                            5,7-Cl.sub.2 [4,5-b]                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   5,7-Cl.sub.2 [4,5-b]                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                                 (d)                                                                             6-NO.sub.2 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   6-NO.sub.2 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                                 (e)                                                                             5-OCH.sub.3 [4,5-b]                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   5-OCH.sub.3 -[4,5-b]                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                                  (f)                                                                            5,6-Cl.sub.2 [4,5-b]                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   5,6-Cl.sub.2 [4,5-b]                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                                 (g)                                                                             6-Br[4,5-b]                                                                              4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   6-Br[4,5-b]                                                                              4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                                 (h)                                                                             5-Cl[4,5-b]                                                                              4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   5-Cl[4,5-b]                                                                              4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                                  (i)                                                                            7-CH.sub.3 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   7-CH.sub.3 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                               222(j)                                                                            6-CH.sub.3 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   6-CH.sub.3 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                                 (k)                                                                             5-CH.sub.3 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-1H                                                                   5-CH.sub.3 [4,5-b]                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                               223(a)                                                                            4-OCH.sub.3 -[4,5-c]                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   4-OCH.sub.3 -[4.5-c]                                                                     4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                                 (b)                                                                             7-Br,6-Cl[4,5-c]                                                                         4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   7-Br,6-Cl[4,5-c]                                                                         4-ClC.sub.6 H.sub.4                                                                     CH.sub. 2                                                                            C(O)  NH.sub.2        --  --                      pyridine-3H                                                                 (c)                                                                             [4,5-c]    4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   [4,5-c]    4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                                 (d)                                                                             4-Cl-[4,5-c]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   4-Cl-[4,5-c]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                                 (e)                                                                             4,6-(Cl.sub.2)-[4,5-c]                                                                   4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   4,6-(Cl.sub.2)-[4,5-c]                                                                   4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                               223(f)                                                                            7-NO.sub.2 -[4,5-c]                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   7-NO.sub.2 -[4,5-c]                                                                      4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                                 (g)                                                                             6-Br,4-Cl[4,5-c]                                                                         4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   6-Br,4-Cl[4,5-c]                                                                         4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                                 (h)                                                                             7-Br-[4,5-c]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   7-Br-[4,5-c]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                                  (i)                                                                            6-Cl-[4,5-c]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-1H                                                                   6-Cl-[4,5-c]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                      pyridine-3H                                                               224(a)                                                                            7-CH.sub.3 -[4,5-b] pyridine-3H                                                          4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR70##                                                                          OC.sub.2 H.sub.5                                                                              --  --                    (b)                                                                             6-CH.sub.3 [4,5-b] pyridine-3H                                                           4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR71##                                                                          OC.sub.2 H.sub.5                                                                              --  --                    (c)                                                                             5-CH.sub.3 -[4,5-b] pyridine-3H                                                          4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR72##                                                                          OC.sub.2 H.sub.5                                                                              --  --                    (d)                                                                             5,6-(CH.sub.3).sub.2 -[4,5-b] pyridine-3H                                                4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR73##                                                                          OC.sub.2 H.sub.5                                                                              --  --                  224(e)                                                                            4-(C.sub.2 H.sub.5).sub.2 N, 6-CH.sub.3 - [4,5-c]pyridine-1H                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR74##                                                                          OC.sub.2 H.sub.5                                                                              --  --                     (f)                                                                            4-CH.sub.3 -[4,5-c] pyridine-1H                                                          4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR75##                                                                          OC.sub.2 H.sub.5                                                                              --  --                    (g)                                                                             5-OCH.sub.3 -[4,5-b] pyridine-3H                                                         4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR76##                                                                          OC.sub.2 H.sub.5                                                                              --  --                  225 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR77##                                                                           C(O)  O(CH.sub.2).sub.2 OH                                                                          (R) --                  226 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR78##                                                                           C(O)  O(CH.sub.2).sub.2                                                                             (R) --                  227 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  NH.sub.2        --  --                  228 [4,5-b]pyridine-3H                                                                       5-Br-furan-2-                                                                           CH.sub.2                                                                             C(O)  NH.sub.2        --  --                                 yl                                                             229 [4,5-b]pyridine-3H                                                                       5-CH.sub.3 -thio-                                                                       CH.sub.2                                                                             C(O)  NH.sub.2        --  --                                 phene-2-yl                                                     230 [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                              C(O) NHCH.sub.3      --  --                  231 [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  232 [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                  233 [4,5-b]pyridine-3H                                                                       4-FC.sub.6 H.sub.4                                                                      CH.sub.2                                                                             C(O)  NH.sub.2        --  H.sub.2 O           234 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                      ##STR79##                                                                           C(O)  NH.sub.2        (S) --                  235 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  --                  236 [4,5-b]pyridine-1H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  C.sub.6 H.sub.5 --  --                  237 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                              ##STR80##                                                                          C.sub.6 H.sub.5 Rac --                  238 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  C.sub.6 H.sub.5 --  --                  239 [4,5-c]pyridine-1H                                                                       4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                  240 5-Cl-[4,5-b]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  OH              --  --                      pyridine-3H                                                               241 5-Cl-[4,5-b]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(C.sub.3 H.sub.7).sub.2                                                                      --  --                      pyridine-3H                                                               242 5-Cl-[4,5-b]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH.sub.2        --  H.sub.2 O               pyridine-3H                                                               243 5-Cl-[4,5-b]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  0.5 H.sub.2 O           pyridine-3H                                                               244 [4,5-b]pyridine-3H                                                                       4-BrC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH[4-N(CH.sub.3).sub.2                                                                        --  --                                                        C.sub.6 H.sub.4]                        245 [4,5-b]pyridine-3H                                                                       4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.2                                                                     C(O)  NH[4-N(CH.sub.3).sub.2                                                                        --  --                                                        C.sub.6 H.sub.4]                        246 5-Cl-[4,5-b]                                                                             4-ClC.sub.6 H.sub.4                                                                     CH.sub.2                                                                             C(O)  NH(CH.sub.3)    --  --                      pyridine-3H                                                               247 5-Cl-[4,5-b]                                                                             4-CH.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  NH(CH.sub.3)    --  --                      pyridine-3H                                                               248 5-Cl-[4,5-b]                                                                             4-CH.sub.3C.sub.6 H.sub.4                                                               CH.sub.2                                                                             C(O)  N(CH.sub.3).sub.2                                                                             --  --                      pyridine-3H                                                               __________________________________________________________________________     *Rac = racemic mixture.                                                       **Metal salt as indicated in W definition.                               

PHARMACOLOGICAL TEST PROCEDURES MUSCLE RELAXANT TEST

The test procedure relied on to indicate positive muscle relexantactivity is the morphine-induced Straub Tail in Mice Test described byG. D. Novak in DRUG DEVELOPMENT RESEARCH (1982) 2: 383-386, except 8animals per group were used per test rather than 10. The test issummarized as follows: The test drug, reference drug, and controlarticles to be administered are prepared in saline, 0.5% aqueousmethylcellulose suspension or other, depending on solubility, in suchconcentration that the volume administered is 10 ml/kg. The initialscreening dose of the test drug is usually 10 mg/kg. Groups of 8 miceare given an IP dose of a compound or vehicle prepared as describedabove. After 15 min, mice are administered morphine sulfate, 60 mg/kg,subcutaneously. Fifteen minutes after administration of morphine (i.e.,30 min after test compound administration), mice were scored forpresence of Straub Tail defined as an elevation of the tail at least 90degrees from the horizontal. An ED₅₀ value may be determined from atleast three logarithmically spaced doses by the method of Litchfield andWilcoxon (1949), J. PHARMACOL. EXP. THER. 96: 99-113. Illustratively,some of more active compounds such as those prepared in Examples 47, 48,56, 90, 243 and 246 exhibited ED₅₀ values of about 1-10 mg/kg in theforegoing Straub Tail Test.

ANTIANXIETY TEST

The test screening procedure relied on to indicate positive antianxietyresponse is a modification of the Vogel Conflict Test which is based onshock-suppressed drinking behavior in rats outlined by J. R. Vogel, etal. in PSYCHOPHARMACOLOGY 21: 1-7 (1971). The procedure used is asfollows: The test reference and control articles to be administeredintraperitoneally in physiological saline, 0.5% aqueous methylcelluloseor other, depending on a solubility in such concentration that thevolume administered is 5 mg/kg. The initial screening dose of the testarticle is usually 100.0 mg/kg initially.

Prior to dosing, rats are housed 2 per cage and deprived of water for 48hr and thereafter randomized into treatment groups of five. Feed isavailable ad libitum. Thirty minutes after dosing, each rat is placedindividually in a plexiglass cage measuring 18 cm in width, 13 cm inheight and 29.5 cm in length and equipped with a stainless steel gridfloor. The cage is covered with a plastic lid containing holes tofacilitate introduction of a water bottle (30 ml plastic centrifugetube) with a rubber stopper and metal drinking tube. A Drinkometercircuit (Omniteck Electronics, Inc., 3000 Cortona Road, Columbus, Ohio43204, is connected between the drinking tube and the grid floor of theapparatus so that the rat completes the circuit whenever it licks thetube. The procedure is to allow the rat to find the drinking tube andcomplete 20 licks (as displayed on the Drinkometer digital readout)prior to the start of the experimental session. Rats not reaching thiscriterion are discarded. A three minute experimental session isinitiated by a 0.25 mA shock at the 20th lick. Rats that continuedrinking will experience a shock at each successive 20th lick. The totalnumber of shocks during the experimental session are recorded asfollows: ##EQU1## Statistical analysis is performed by the Dunn'sMultiple Comparison Test described by O. J. Dunn (1964) TECHNOMETRICS6(3):241-52. The mean number of shocks experienced by the control groupis compared with those of each drug-treated group. Significance isconsidered at P<0.1. The higher the total shocks compared to control,the more active is the compound. Active compounds may then be similarlytested at reduced dosages. Five rats were tested at a given dosage leveland 5 rats were used as controls. Illustratively, some of the moreactive compounds such as those of Examples 47, 65, 74, 82, 86, 88, 246,247 and 248 have significant activity in the foregoing Vogel test at 10mg/kg.

Anticonvulsant activity was determined for compounds of Formula I asevidenced by using chemical or electrical challenge as follows:

METRAZOLE CHEMICAL CHALLENGE (SWINYARD METHOD)

Groups of 8 adult female mice were randomly assigned to dosage groupsaccording to the method of Steel, R. G. D., and Torrie, J. H. (1960) in"Principles and Procedures of Statistics", McGraw-Hill Book Company,Inc., pp 99-100, pp 428-31. Each mouse was identified with a color codeon its tail. The test compounds were administered as solutions orsuspensions in 10 ml/kg mouse body weight of 0.5% aqueous methylcellulose within 15 minutes of preparation of the suspension. Metrazole®(pentylenetetrazol) was prepared as a solution in physiological saline.The mice were not fasted prior to the test. Eight mice were tested ateach dosage level.

Each mouse received one dose of the test drug (usually 100 mg/kg forscreening) in the 0.5% aqueous methylcellulose or the control article(0.5% aqueous methylcellulose alone) intraperitoneally. Metrazole (80mg/kg S. C.) was then given in a loose fold of skin on the back of theneck; i.e., 1/2 hr after the test compound or control article was given.Injections were given with a 1 ml glass tuberculin syringe withappropriate size hypodermic needle (27 gauge for solutions; 23 gauge forsuspensions). All injections were given in a volume of 10 ml/kg mousebody weight. Each mouse was observed for 30 minutes following Metrazoleinjection. Failure of the animals to exhibit a threshold seizure (asingle episode of clonic spasms at least 5 seconds in duration) wasdefined as protection. Anticonvulsant data were tabulated as the presentprotection, i.e., ##EQU2## The ED₅₀, 95% confidence limits and potencyratio may be ascertained by the computer-based probit analysis ascribedto Finney, D. J. (1964) Statistical Method in Biological Assay, 2nd Ed.,New York. Hefner Publishing Co. Illustratively, some of the more activecompounds such as those of Examples 30, 48, 56, 242, 243, 246, 247 and248 exhibit ED₅₀ values of about 1-10 mg/kg in the foregoing metrazoletest.

ELECTRICAL CHALLENGE

Adult female mice in groups of eight were administered the test drugintraperitoneally (usually 100 mg/kg initially for screening) in liquidcarrier, usually physiological saline or water. Animals were challengedelectrically by placing brass electrodes on the corneas and applying anelectrical stimulus (60 Hz, 5 m sec. pulse width, 34 m A intensity) for0.2 seconds by way of a Grass Stimulator® and constant current unit anda Hunter Timer®. The absence of tonic seizures upon cessation of thestimuli was scored as protection in that animal. The number of animalsprotected from tonic seizures at a given dose of test drug wasdetermined. The ED₅₀, 95% confidence limits and potency ratio may beascertained by the method of J. T. Litchfield and F. Wilcoxon (1949) J.PHARMACOL. EXP. THER. 96, 99-113. Illustratively, some of the moreactive compounds such as those of Example 47, 48, 56, 90 and 243 exhibitED₅₀ values in the range of about 2-15 mg/kg.

PHARMACEUTICAL COMPOSITIONS

The methods of treating anxiety, muscle tension, and spasticity inmammals is best carried out by administering as active ingredients in apharmaceutical composition at least one of the compounds of Formula I inassociation with a pharmaceutical carrier or excipient. The compoundsare thus presented in a therapeutic composition suitable for oral,rectal, parenteral, subcutaneous, intramuscular, intraperitoneal, orintravenous administration. Thus, for example, the composition for oraladministration can take the form of elixirs, capsules, tablets, orcoated tablets containing carriers conveniently used in thepharmaceutical art. Suitable tableting excipients include lactose,potato and maize starches, talc, gelatin, stearic and silicic acids,magnesium stearate and polyvinyl pyrrolidone.

For parenteral administration the carrier can be comprised of a sterileparenterally acceptable liquid; e.g., water or arachis oil contained inampoules.

In compositions for rectal administration, the carrier can be comprisedof a suppository base; e.g., cocoa butter or glyceride.

Advantageously, the compositions are formulated as dosage units, eachunit being adapted to supply a fixed dose of active ingredients.Tablets, coated tablets, capsules, ampoules and suppositories areexamples of preferred dosage forms according to the invention. It isonly necessary that the active ingredient constitute an effectiveamount; i.e., such that a suitable effective dosage will be consistentwith the dosage form employed. The exact individual dosages as well asdaily dosages will, of course, be determined according to standardmedical principles under the direction of a physician or veterinarian.

Animal testing suggests that the more active compounds of Formula I willbe effective in humans for muscle relaxant effects at about 1 to 20mg/kg body weight per day. Thus, an active compound such as that ofExample 243 may be administered to effectively control muscle spasms inunit dosage form to an adult human at about 75-200 mg once or twice aday.

Animal testing suggests that the more active compounds of Formula I suchas those cited above in the Vogel test will be effective in humans forthe relief from anxiety at about 4 to 40 mg administered once or twicedaily.

The compounds of Formula I have anticonvulsant property as exhibited byactivity against seizures caused by electrical or chemical challenge.The animal data suggest the more active compounds of Formula I, such asthose cited above under Electroshock Experiments, have anticonvulsantactivity ranging from about 1.5 to 10 times that of phenobarbital. Theanimal data suggest the more active compounds of Formula I, such asthose cited above under Metrazole Chemical Challenge, haveanticonvulsant activity ranging from about 10 to 100 times that ofvalproic acid. The more active compounds of Formula I are projected tobe effective in all types of epilepsy, both grand mal and petit mal,seizures. For example, oral daily doses of about 2-75 mg of the activeagent 3 times a day are projected for treatment of epilepsy.

The active ingredients of the invention may be combined with otherpharmacologically active agents as previously indicated, or withbuffers, antacids or the like, for administration and the proportion ofthe active agent in the composition may be varies widely.

CAPSULES

Capsules of 5 mg, 25 mg, and 50 mg of active ingredient per capsule areprepared; with higher amounts of ingredient reduction may be made in theamount of lactose.

    ______________________________________                                        Typical blend for encapsulation                                                                    Per Capsule, mg.                                         ______________________________________                                        Active ingredient     5.0                                                     Lactose               296.7                                                   Starch                129.0                                                   Magnesium stearate    4.3                                                     Total                 435.0   mg.                                             ______________________________________                                    

Uniformly blend the selected active ingredient with lactose, starch andmagnesium stearate and encapsulate the blend.

Additional capsule formulations preferably contain higher dose of activeingredient and are as follows:

    ______________________________________                                                     100 mg. per                                                                             250 mg. per 500 mg. per                                Ingredients  Capsule   Capsule     Capsule                                    ______________________________________                                        Active ingredient                                                                          100.0     250.0       500.0                                      Lactose      231.5     126.5       31.1                                       Starch       99.2      54.2        13.4                                       Magnesium stearate                                                                         4.3       4.3         5.5                                        Total, mg.   435.0     435.0       550.0                                      ______________________________________                                    

TABLETS

A typical formulation for a tablet containing 5.0 mg of activeingredient per tablet follows. The formulation may be used for otherstrengths of active ingredient by adjustment of weight of dicalciumphosphate.

    ______________________________________                                        Ingredients          Per Tablet, mg.                                          ______________________________________                                        (1) Active ingredient                                                                              5.0                                                      (2) Corn Starch      13.6                                                     (3) Corn Starch (paste)                                                                            3.4                                                      (4) Lactose          79.2                                                     (5) Dicalcium phosphate                                                                            68.0                                                     (6) Calcium Stearate 0.9                                                      Total                170.1    mg.                                             ______________________________________                                    

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water.Granulate the blend with the starch paste and pass the wet mass througha number eight mesh screen. The wet granulation is dried and passedthrough a number twelve mesh screen. The dried granules are blended withcalcium stearate and compressed.

Additional tablet formulations preferably contain a higher dosage of theactive ingredient and are as follows:

    ______________________________________                                        50 mg. Tablet                                                                 Ingredients     Per Tablet, mg.                                               ______________________________________                                        Active ingredient                                                                             50.0                                                          Lactose         90.0                                                          Corn Starch     58.0                                                          Calcium stearate                                                                              2.0                                                           Total           200.0                                                         ______________________________________                                    

Uniformly blend the active ingredient, lactose, and corn starch. Theblend is granulated, using water as a granulating medium. The wetgranules are passed through an eight mesh screen and dried at 140 to 160degrees Fahrenheit overnight. The dried granules are passed through anumber ten mesh screen and blended with the proper amount of calciumstearate and this blend is then converted into tablets on a suitabletablet press.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, methods, processes andpharmaceutical compositions of the present invention without departingfrom the spirit and scope thereof; and it is therefore to be understoodthat the invention is to be limited only by the scope of the appendedclaims.

What is claimed is:
 1. A method for the treatment of a living animalbody for muscle tension and spasticity and/or anxiety and/or convulsionswhich comprises administering a compound selected from the group havingthe formula: ##STR81## wherein A represents a heterocyclic ring havingtwo of its carbon atoms held mutually with the imidazo moiety selectedfrom the group consisting of pyridine in any of its four positionswherein nitrogen is unshared by the imidazo moiety and substituted byone or two Z radicals on a carbon not shared by the imidazo moietyselected from the group consisting of hydrogen, halogen, loweralkyl,hydroxy, loweralkoxy, diloweralkylamino or nitro;n is 1 to 3; R⁶ ishydrogen or loweralkyl; Ar is selected from: ##STR82## B is carbonyl; Wis selected from:hydrogen, loweralkyl (Y)₁₋₃ -phenyl, (Y)₁₋₃-phenyl-loweralkyl, --OR¹, --OM, --O(CH₂)_(p) --OH, --NR² (CH₂)_(p)COOR¹, --NR² (CH₂)_(p) COOM or --NR² [(CH₂)_(p) NHC(O)R¹ ],wherein R¹and R² are selected from hydrogen, loweralkyl, (Y)₁₋₃ -phenyl, or (Y)₁₋₃-phenyl-loweralkyl; p is 0-3;wherein all of the above Y is hydrogen,halo, loweralkoxy, loweralkyl, trifluoromethyl, cyano, nitro ordiloweralkylamino; M is a pharmaceutically acceptable metal, forming anacid salt; the optical isomers, the oxides represented by O and thepharmaceutically acceptable acid addition salts thereof.